CN1353694A - Alpha-substituted carboxylic acid derivatives - Google Patents

Abstract

The alpha-substituted carboxylic acid derivatives having the formula (I): wherein R1 is an alkyl group, etc., R2 is a hydrogen atom, etc., R3 is a hydrogen atom, etc., A is =CH-group, etc., B is an oxygen atom, etc., W1 is a C1-C8 alkylene group, W2 is a single bond or a C1-C8 alkylene group, X is a hydrogen atom, etc., Y is an oxygen atom, etc., and Z1 is an alkoxy group, etc., and pharmacologically acceptable salts, esters and amides thereof are useful for treatment and/or prevention of diabetes mellitus, impaired glucose tolerance, gestational diabetes mellitus, or the like.

Description

α-Substituted Carboxylic Acid Derivatives

[technical field]

The present invention relates to an effect of improving insulin resistance, hypoglycemic effect, anti-inflammation effect, immunoregulatory effect, aldose reductase inhibitory effect, 5-lipoxygenase inhibitory effect, lipid peroxidation production inhibitory effect, PPAR activation effect , anti-osteoporosis, leukotriene antagonism, adipocyte promotion, cancer cell proliferation inhibition, calcium antagonism α-substituted carboxylic acid derivatives, related to its pharmaceutically acceptable esters, pharmaceutical An acceptable amide or a pharmaceutically acceptable salt thereof.

Furthermore, the present invention relates to the prevention and/or treatment of the above α-substituted carboxylic acid derivatives, their pharmaceutically acceptable esters or their pharmaceutically acceptable amides or their pharmaceutically acceptable salts as active ingredients, for preventing and/or treating such as Diabetes, hyperlipidemia, obesity, glucose intolerance, hypertension, fatty liver, complications of diabetes (such as retinopathy, nephropathy, neuropathy, cataract, coronary artery disease, etc.), arteriosclerosis, gestational diabetes, polycystic ovary Syndrome, cardiovascular diseases (such as ischemic heart disease, etc.), cell damage caused by atherosclerosis or ischemic heart disease (such as brain damage caused by stroke, etc.), gout, inflammatory diseases (such as bone Arthritis, pain, fever, rheumatoid arthritis, inflammatory bowel disease, acne, sunburn, psoriasis, eczema, allergic disease, asthma, GI ulcer, cachexia, autoimmune disease, pancreatitis, etc.), cancer, osteoporosis Drugs for diseases such as cataracts and cataracts.

Moreover, the present invention relates to a compound consisting of the above-mentioned α-substituted carboxylic acid derivatives, their pharmaceutically acceptable esters or their pharmaceutically acceptable amides or their pharmaceutically acceptable salts, and sulfonylurea, α-glucose Glycosidase inhibitors, aldose reductase inhibitors, biguanides, statin (statin; statin) compounds, squalene synthesis inhibitors, fibrate (fibrate) compounds, LDL dissimilation accelerators, angiotensin A pharmaceutical composition composed of at least one of II antagonists, angiotensin-converting enzyme inhibitors, antineoplastic agents and RXR activators (RXR agonists) (particularly preferably for the prevention and/or treatment of diabetes or diabetic complications drug).

[Background technique]

In (1) JP-8-504194, (2) JP-10-501222, (3) JP-10-504808, (4) JP-10-114751, (5) )WO98/31359A describes a part of the compound α-substituted carboxylic acid derivatives involved in the present application. However, the compounds described in these gazettes differ from the present invention in terms of their actions or their purpose of anti-platelet aggregation, inhibition of osteoclast-mediated bone resorption, treatment of osteoporosis, and the like.

In addition, compounds having effects such as treating diabetes and lowering blood sugar are described in (6) WO 97/31907. However, although the compounds described in the publication may also have one of the structural characteristics of the compounds of the present application, that is, have a benzimidazole structure, there is no substituent on the benzene ring of the benzimidazole structure in the publication, or even if there is a substitution Partially, the substituents are only lower alkyl groups. On the other hand, the compounds of the present application are different from the compounds described in the above-mentioned gazettes in view of having a relatively large substituent moiety on the benzene ring of the benzimidazole or imidazopyridine structure.

Furthermore, compounds having a therapeutic effect on diabetes are described in (7) WO 99/29640. However, although the compounds described in this publication may also be α-carboxylic acids having a benzimidazole structure similar to the compound of the present application, in this case, since the substituted moiety at the α position is amino, alkylcarbonyl, or alkoxy A protecting group such as a carbonyl group is relatively easy to remove, so it is different from the compound of the present application. In addition, the compound described in the above-mentioned gazette also differs from the invention of the present application in that it has an action of fibroblast growth factor antagonism.

[Disclosure of Invention]

The present inventors have been exploring a series of α-substituted carboxylic acid derivatives, their pharmaceutically acceptable esters or their pharmaceutically acceptable amides or their pharmaceutically acceptable salts for a long time, and their synthesis and Pharmacological activity was studied, and it was found that α-substituted carboxylic acid derivatives have excellent insulin resistance improvement effects, hypoglycemic effects, anti-inflammatory effects, immune regulation effects, aldose reductase inhibitory effects, and 5-lipoxygenase inhibitory effects , lipid peroxidation production inhibition, PPAR activation, anti-osteoporosis, leukotriene antagonism, adipocyte transformation promotion, cancer cell proliferation inhibition, calcium antagonism, and the side effects are also very small, and it was also found that The present invention has been accomplished by discovering that α-substituted carboxylic acid derivatives are characterized by high fat solubility.

Another object of the present invention is to provide a preventive and/or therapeutic Such as diabetes, hyperlipidemia, obesity, glucose intolerance, hypertension, fatty liver, complications of diabetes (such as retinopathy, nephropathy, neuropathy, cataract, coronary artery disease, etc.), arteriosclerosis, gestational diabetes, polycystic Ovarian syndrome, cardiovascular diseases (such as ischemic heart disease, etc.), cell damage caused by atherosclerosis or ischemic heart disease (such as brain damage caused by stroke, etc.), gout, inflammatory diseases (such as Osteoarthritis, pain, fever, rheumatoid arthritis, inflammatory bowel disease, acne, sunburn, psoriasis, eczema, allergic disease, asthma, GI ulcer, cachexia, autoimmune disease, pancreatitis, etc.), cancer, osteoarthritis Drugs for diseases such as osteoporosis and cataracts.

In addition, another object of the present invention is to provide a compound consisting of the above-mentioned α-substituted carboxylic acid derivatives, their pharmaceutically acceptable esters or their pharmaceutically acceptable amides or their pharmaceutically acceptable salts, and sulfonylurea , α-glucosidase inhibitors, aldose reductase inhibitors, biguanides, statins, squalene synthesis inhibitors, fibrates, LDL dissimilation promoters, angiotensin II antagonists, angiotensin conversion A pharmaceutical composition composed of at least one of an enzyme inhibitor, an antineoplastic drug and an RXR activator (especially preferably a drug for the prevention and/or treatment of diabetes or diabetic complications).

The present invention relates to α-substituted carboxylic acid derivatives with general formula (I), (II), (III) or (IV), their pharmaceutically acceptable esters or their pharmaceutically acceptable amides or their pharmaceutically acceptable acceptable salt.

[in

R ₁ , R ₂ and R ₃ are the same or different, and represent (i) hydrogen atom, (ii) C ₁ -C ₆ alkyl group, (iii) C ₆ -C ₁₀ aryl group (may have 1-5 following substitutions moiety α ₁ ), (iv) C ₇ -C ₁₆ aralkyl (the aryl group may have 1-5 substituent moieties α ₁ described below), (v) C ₁ -C ₆ alkylsulfonyl, (vi ) C ₁ -C ₆ haloalkylsulfonyl, (vii) C ₆ -C ₁₀ arylsulfonyl (may have 1-5 substituents α ₁ ) or (viii) C ₇ -C ₁₆ aralkylsulfonyl an acyl group (the aryl group may have 1-5 substituent moieties α ₁ described below),

A represents a nitrogen atom or =CH-group,

B represents an oxygen atom or a sulfur atom,

W ₁ represents a C ₁ -C ₈ alkylene group,

W ₂ represents a single bond or a C ₁ -C ₈ alkylene group,

X represents (i) hydrogen atom, (ii) C ₁ -C ₆ alkyl, (iii) C ₁ -C ₆ haloalkyl, (iv) C ₁ -C ₆ alkoxy, (v) halogen atom, (vi ) hydroxyl group, (vii) cyano group, (viii) nitro group, (ix) C ₃ -C ₁₀ cycloalkyl group, (x) C ₆ -C ₁₀ aryl group (may have 1-5 substituent moieties β as follows) , (xi) C ₇ -C ₁₆ aralkyl (the aryl may have 1-5 substituents β as described below), (xii) C ₁ -C ₇ aliphatic acyl, (xiii) C ₄ -C ₁₁ Cycloalkylcarbonyl, (xiv) C ₇ -C ₁₁ arylcarbonyl (may have 1-5 following substituent moieties β), (xv) C ₈ -C ₁₇ aralkylcarbonyl (may have 1 on aryl -5 substituent moieties β below), (xvi) monocyclic heteroaryl ring carbonyl (may have 1 to 5 substituent moieties β below), (xvii) carbamoyl, (xviii) C ₇ -C ₁₁ Arylaminocarbonyl (the aryl group may have 1-5 substituents β below) or (xix) amino (can have 1 or 2 substituents β below),

Y represents an oxygen atom or an S(O)p group (p represents an integer of 0-2 in the formula),

Z ₁ represents (i) hydrogen atom, (ii) C ₁ -C ₆ alkyl group, (iii) C ₁ -C ₆ alkoxy group, (iv) C ₁ -C ₆ alkylthio group, (v) halogen atom, (vi) C ₆ -C ₁₀ aryl (may have 1-5 substituents α ₁ described below), (vii) C ₇ -C ₁₆ aralkyl (may have 1-5 substituents described below on aryl Moiety α ₁ ), (viii) C ₆ -C ₁₀ aryloxy group (may have 1-5 substituent moieties α ₁ described below), (ix) C ₇ -C ₁₆ aralkyloxy group (may have 1-5 of the following substituted moieties α ₁ ), (x) C ₃ -C ₁₀ cycloalkoxy, (xi) C ₃ -C ₁₀ cycloalkylthio, (xii) saturated heterocyclic oxy group (may have 1 -5 substituted moieties α ₁ ), (xiii) monocyclic heteroaryl epoxy group (may have 1-5 substituted moieties α ₁ ), (xiv) C ₆ -C ₁₀ arylthio ( may have 1 to 5 of the following substituent moieties α ₁ ), (xv) C ₇ -C ₁₆ aralkylthio (may have 1 to 5 of the following substituent moieties α ₁ on the aryl group), (xvi) saturated hetero Cyclothio group (may have 1 to 5 substituents α ₁ described below), (xvii) monocyclic heteroaryl ring thio group (may have 1 to 5 substituents α ₁ described below), (xviii) amino ( may have 1 or 2 of the following substituted moieties (α ₁ ) or (xix) hydroxyl groups,

The substituent moiety _α1 represents (i) C ₁ -C ₆ alkyl, (ii) C ₁ -C ₆ haloalkyl, (iii) C ₁ -C ₆ alkoxy, (iv) halogen atom, (v) Hydroxy, (vi) cyano, (vii) nitro, (viii) C ₃ -C ₁₀ cycloalkyl, (ix) C ₆ -C ₁₀ aryl (may have 1 to 5 substituents β below), (x) C ₇ -C ₁₆ aralkyl group (the aryl group may have 1-5 substituents β as described below), (xi) C ₁ -C ₇ aliphatic acyl group, (xii) C ₄ -C ₁₁ ring Alkylcarbonyl, (xiii) C ₇ -C ₁₁ arylcarbonyl (may have 1-5 following substituting moieties β), (xiv) C ₈ -C ₁₇ aralkylcarbonyl (may have 1- 5 of the following substituent moieties β), (xv) monocyclic heteroaryl ring carbonyl (may have 1 to 5 of the following substituting moieties β), (xvi) carbamoyl, (xvii) C ₇ -C ₁₁ aryl Aminocarbonyl (may have 1-5 substituents β below on the aryl), (xviii) amino (can have 1 or 2 substituents β below) or (xix) carboxyl,

The substituent moiety β represents (i) C ₁ -C ₁₀ alkyl group, (ii) halogen atom, (iii) C ₆ -C ₁₀ aryl group (may have 1-5 substituent moieties γ below), (iv) C ₇ -C ₁₆ aralkyl (the aryl may have 1-5 substituents γ as follows), (v) C ₁ -C ₇ aliphatic acyl, (vi) C ₇ -C ₁₁ arylcarbonyl (can Having 1-5 of the following substituents γ), (vii) C ₈ -C ₁₇ aralkylcarbonyl (the aryl may have 1-5 of the following substituting γ), (viii) C ₄ -C ₁₁ Cycloalkylcarbonyl, (ix) monocyclic type heteroaryl ring carbonyl (may have 1 to 5 substituent moieties γ described below), (x) carbamoyl or (xi) C ₇ -C ₁₁ arylaminocarbonyl ( On the aryl group, there may be 1-5 substituent moieties γ) described below,

The substituent moiety γ represents a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group, a halogen atom or a hydroxyl group];

[in

R ₁ , R ₂ and R ₃ are the same or different, and represent (i) hydrogen atom, (ii) C ₁ -C ₆ alkyl group, (iii) C ₆ -C ₁₀ aryl group (may have 1-5 following substitutions moiety α ₁ ), (iv) C ₇ -C ₁₆ aralkyl (the aryl group may have 1-5 substituent moieties α ₁ described below), (v) C ₁ -C ₆ alkylsulfonyl, (vi ) C ₁ -C ₆ haloalkylsulfonyl, (vii) C ₆ -C ₁₀ arylsulfonyl (may have 1-5 substituents α ₁ ) or (viii) C ₇ -C ₁₆ aralkylsulfonyl an acyl group (the aryl group may have 1-5 substituent moieties α ₁ described below),

A represents a nitrogen atom or =CH-group,

B represents an oxygen atom or a sulfur atom,

W ₁ represents a C ₁ -C ₈ alkylene group,

W ₂ represents a single bond or a C ₁ -C ₈ alkylene group,

X represents (i) hydrogen atom, (ii) C ₁ -C ₆ alkyl, (iii) C ₁ -C ₆ haloalkyl, (iv) C ₁ -C ₆ alkoxy, (v) halogen atom, (vi ) hydroxyl group, (vii) cyano group, (viii) nitro group, (ix) C ₃ -C ₁₀ cycloalkyl group, (x) C ₆ -C ₁₀ aryl group (may have 1-5 substituent moieties β as follows) , (xi) C ₇ -C ₁₆ aralkyl (the aryl may have 1-5 substituents β as described below), (xii) C ₁ -C ₇ aliphatic acyl, (xiii) C ₄ -C ₁₁ Cycloalkylcarbonyl, (xiv) C ₇ -C ₁₁ arylcarbonyl (may have 1-5 following substituent moieties β), (xv) C ₈ -C ₁₇ aralkylcarbonyl (may have 1- 5 of the following substituent moieties β), (xvi) monocyclic heteroaryl ring carbonyl (may have 1 to 5 of the following substituting moieties β), (xvii) carbamoyl, (xviii) C ₇ -C ₁₁ aryl Aminocarbonyl (can have 1-5 substituents β below on the aryl group) or (xix) amino (can have 1 or 2 substituents β below),

Y represents an oxygen atom or an S(O)p group (wherein p is an integer of 0-2),

Z ₂ represents a saturated heterocyclic ring (may have 1-5 substituents α ₁ described below) or a C ₆ -C ₁₀ aryl group (may have 1-5 substituents α ₂ described below),

The substituent moiety _α1 represents (i) C ₁ -C ₆ alkyl, (ii) C ₁ -C ₆ haloalkyl, (iii) C ₁ -C ₆ alkoxy, (iv) halogen atom, (v) Hydroxy, (vi) cyano, (vii) nitro, (viii) C ₃ -C ₁₀ cycloalkyl, (ix) C ₆ -C ₁₀ aryl (may have 1 to 5 substituents β below), (x) C ₇ -C ₁₆ aralkyl group (the aryl group may have 1-5 substituents β as described below), (xi) C ₁ -C ₇ aliphatic acyl group, (xii) C ₄ -C ₁₁ ring Alkylcarbonyl, (xiii) C ₇ -C ₁₁ arylcarbonyl (may have 1-5 following substituent moieties β), (xiv) C ₈ -C ₁₇ aralkylcarbonyl (may have 1-5 the following substituent moieties β), (xv) monocyclic heteroaryl ring carbonyl (may have 1 to 5 substituent moieties β below), (xvi) carbamoyl group, (xvii) C ₇ -C ₁₁ aryl Aminocarbonyl (may have 1-5 substituents β below on the aryl group), (xviii) amino (may have 1 or 2 substituents β below) or (xix) carboxyl,

The substituent moiety α ₂ represents (i) C ₃ -C ₁₀ cycloalkyl, (ii) C ₆ -C ₁₀ aryl (may have 1-5 substituent moieties β below), (iii) C ₇ -C ₁₆ aralkyl groups (the aryl groups may have 1-5 substituents β as described below), (iv) C ₁ -C ₇ aliphatic acyl groups, (v) C ₄ -C ₁₁ cycloalkylcarbonyl groups, (vi) C ₇ -C ₁₁ arylcarbonyl (may have 1-5 substituents β below), (vii) C ₈ -C ₁₇ aralkylcarbonyl (may have 1-5 substituents β below on aryl) , (viii) monocyclic heteroaryl ring carbonyl (may have 1-5 substituents β below) or (ix) C ₇ -C ₁₁ arylaminocarbonyl (may have 1-5 substituents below The above substituting part β),

The substituent moiety β represents (i) C ₁ -C ₁₀ alkyl group, (ii) halogen atom, (iii) C ₆ -C ₁₀ aryl group (may have 1-5 substituent moieties γ below), (iv) C ₇ -C ₁₆ aralkyl (the aryl may have 1-5 substituents γ as follows), (v) C ₁ -C ₇ aliphatic acyl, (vi) C ₇ -C ₁₁ arylcarbonyl (can Having 1-5 of the following substituents γ), (vii) C ₈ -C ₁₇ aralkylcarbonyl (the aryl may have 1-5 of the following substituting γ), (viii) C ₄ -C ₁₁ Cycloalkylcarbonyl, (ix) monocyclic type heteroaryl ring carbonyl (may have 1 to 5 substituent moieties γ described below), (x) carbamoyl or (xi) C ₇ -C ₁₁ arylaminocarbonyl ( On the aryl group, there may be 1-5 substituent moieties γ) described below,

The substituent moiety γ represents a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group, a halogen atom or a hydroxyl group];

[in

R ₁ , R ₂ and R ₃ are the same or different, and represent (i) hydrogen atom, (ii) C ₁ -C ₆ alkyl group, (iii) C ₆ -C ₁₀ aryl group (may have 1-5 following substitutions moiety α ₁ ), (iv) C ₇ -C ₁₆ aralkyl (the aryl group may have 1-5 substituent moieties α ₁ described below), (v) C ₁ -C ₆ alkylsulfonyl, (vi ) C ₁ -C ₆ haloalkylsulfonyl, (vii) C ₆ -C ₁₀ arylsulfonyl (may have 1-5 substituents α ₁ ) or (viii) C ₇ -C ₁₆ aralkylsulfonyl an acyl group (the aryl group may have 1-5 substituent moieties α ₁ described below),

A represents a nitrogen atom or =CH-group,

B represents an oxygen atom or a sulfur atom,

W ₁ represents a C ₁ -C ₈ alkylene group,

W ₂ represents a single bond or a C ₁ -C ₈ alkylene group,

X represents (i) hydrogen atom, (ii) C ₁ -C ₆ alkyl, (iii) C ₁ -C ₆ haloalkyl, (iv) C ₁ -C ₆ alkoxy, (v) halogen atom, (vi ) hydroxyl group, (vii) cyano group, (viii) nitro group, (ix) C ₃ -C ₁₀ cycloalkyl group, (x) C ₆ -C ₁₀ aryl group (may have 1-5 substituent moieties β as follows) , (xi) C ₇ -C ₁₆ aralkyl (the aryl may have 1-5 substituents β as described below), (xii) C ₁ -C ₇ aliphatic acyl, (xiii) C ₄ -C ₁₁ Cycloalkylcarbonyl, (xiv) C ₇ -C ₁₁ arylcarbonyl (may have 1-5 following substituent moieties β), (xv) C ₈ -C ₁₇ aralkylcarbonyl (may have 1- 5 substituent moieties below β), (xvi) monocyclic heteroaryl ring carbonyl (may have 1 to 5 substituent moieties below β), (xvii)) carbamoyl, (xvii) C ₇ -C ₁₁ Arylaminocarbonyl (the aryl group may have 1-5 substituents β below) or (xix) amino (can have 1 or 2 substituents β below),

Y represents an oxygen atom or an S(O)p group (wherein p represents an integer of 0-2),

Z ₃ represents (i) C ₁ -C ₆ alkyl, (ii) C ₆ -C ₁₀ aryl (may have 1-5 substituents α ₁ as follows), (iii) C ₇ -C ₁₆ aralkyl (the aryl group may have 1-5 substituents α ₁ described below), (iv) C ₃ -C ₁₀ cycloalkyl or (v) saturated heterocyclic group (may have 1-5 substituents described below α ₁ ),

The substituent moiety _α1 represents (i) C ₁ -C ₆ alkyl, (ii) C ₁ -C ₆ haloalkyl, (iii) C ₁ -C ₆ alkoxy, (iv) halogen atom, (v) Hydroxy, (vi) cyano, (vii) nitro, (viii) C ₃ -C ₁₀ cycloalkyl, (ix) C ₆ -C ₁₀ aryl (may have 1 to 5 substituents β below), (x) C ₇ -C ₁₆ aralkyl group (the aryl group may have 1-5 substituents β as described below), (xi) C ₁ -C ₇ aliphatic acyl group, (xii) C ₄ -C ₁₁ ring Alkylcarbonyl, (xiii) C ₇ -C ₁₁ arylcarbonyl (may have 1-5 following substituent moieties β), (xiv) C ₈ -C ₁₇ aralkylcarbonyl (may have 1-5 the following substituent moieties β), (xv) monocyclic heteroaryl ring carbonyl (may have 1 to 5 substituent moieties β below), (xvi) carbamoyl group, (xvii) C ₇ -C ₁₁ aryl Aminocarbonyl (may have 1-5 substituents β below on the aryl group), (xviii) amino (may have 1 or 2 substituents β below) or (xix) carboxyl,

The substituent moiety β represents (i) C ₁ -C ₁₀ alkyl group, (ii) halogen atom, (iii) C ₆ -C ₁₀ aryl group (may have 1-5 substituent moieties γ below), (iv) C ₇ -C ₁₆ aralkyl (the aryl may have 1-5 substituents γ as follows), (v) C ₁ -C ₇ aliphatic acyl, (vi) C ₇ -C ₁₁ arylcarbonyl (can Having 1-5 of the following substituents γ), (vii) C ₈ -C ₁₇ aralkylcarbonyl (the aryl may have 1-5 of the following substituting γ), (viii) C ₄ -C ₁₁ Cycloalkylcarbonyl, (ix) monocyclic type heteroaryl ring carbonyl (may have 1 to 5 substituent moieties γ described below), (x) carbamoyl or (xi) C ₇ -C ₁₁ arylaminocarbonyl ( On the aryl group, there may be 1-5 substituent moieties γ) described below,

The substituent moiety γ represents a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group, a halogen atom or a hydroxyl group];

[in

R ₁ , R ₂ and R ₃ are the same or different, and represent (i) hydrogen atom, (ii) C ₁ -C ₆ alkyl group, (iii) C ₆ -C ₁₀ aryl group (may have 1-5 following substitutions moiety α ₁ ), (iv) C ₇ -C ₁₆ aralkyl (the aryl group may have 1-5 substituent moieties α ₁ described below), (v) C ₁ -C ₆ alkylsulfonyl, (vi ) C ₁ -C ₆ haloalkylsulfonyl, (vii) C ₆ -C ₁₀ arylsulfonyl (may have 1-5 substituents α ₁ ) or (viii) C ₇ -C ₁₆ aralkylsulfonyl an acyl group (the aryl group may have 1-5 substituent moieties α ₁ described below),

R ₄ represents (i) C ₁ -C ₆ alkyl, (ii) C ₆ -C ₁₀ aryl (may have 1-5 substituents α ₁ described below) or (iii) C ₇ -C ₁₆ aralkyl (the aryl group may have 1-5 substituents α ₁ described below),

A represents a nitrogen atom or =CH-group,

B represents an oxygen atom or a sulfur atom,

W ₁ represents a C ₁ -C ₈ alkylene group,

W ₂ represents a single bond or a C ₁ -C ₈ alkylene group,

X represents (i) hydrogen atom, (ii) C ₁ -C ₆ alkyl, (iii) C ₁ -C ₆ haloalkyl, (iv) C ₁ -C ₆ alkoxy, (v) halogen atom, (vi ) hydroxyl group, (vii) cyano group, (viii) nitro group, (ix) C ₃ -C ₁₀ cycloalkyl group, (x) C ₆ -C ₁₀ aryl group (may have 1-5 substituent moieties β as follows) , (xi) C ₇ -C ₁₆ aralkyl (the aryl may have 1-5 substituents β as described below), (xii) C ₁ -C ₇ aliphatic acyl, (xiii) C ₄ -C ₁₁ Cycloalkylcarbonyl, (xiv) C ₇ -C ₁₁ arylcarbonyl (may have 1-5 following substituent moieties β), (xv) C ₈ -C ₁₇ aralkylcarbonyl (may have 1- 5 of the following substituent moieties β), (xvi) monocyclic heteroaryl ring carbonyl (may have 1 to 5 of the following substituting moieties β), (xvii) carbamoyl, (xviii) C ₇ -C ₁₁ aryl Aminocarbonyl (can have 1-5 substituents β below on the aryl group) or (xix) amino (can have 1 or 2 substituents β below),

Y represents an oxygen atom or an S(O)p group (wherein p represents an integer of 0-2),

Z ₄ represents (i) C ₁ -C ₆ alkoxyl group, (ii) C ₁ -C ₆ alkylthio group, (iii) halogen atom, (iv) C ₆ -C ₁₀ aryl group (can have 1-5 The following substituent moieties α ₁ ), (v) C ₇ -C ₁₆ aralkyl groups (the aryl group may have 1-5 substituent moieties α ₁ ), (vi) C ₆ -C ₁₀ aryloxy groups ( may have 1 to 5 of the following substituents α ₁ ), (vii) C ₇ -C ₁₆ aralkyloxy (may have 1 to 5 of the following substituents α ₁ on the aryl group), (viii) C ₃ -C ₁₀ cycloalkoxy, (ix) C ₃ -C ₁₀ cycloalkylthio, (x) saturated heterocyclic oxy group (may have 1 to 5 substituents α ₁ ), (xi) monocyclic type The heteroaryl epoxy group (may have 1-5 substituent moieties α ₁ described below), (xii) C ₆ -C ₁₀ arylthio group (may have 1-5 substituent moieties α ₁ described below), (xiii) C ₇ -C ₁₆ aralkylthio (the aryl group may have 1-5 substituents α ₁ described below), (xiv) saturated heterocyclic thio group (may have 1-5 substituents α ₁ described below) , (xv) monocyclic heteroaryl ring thio group (may have 1 to 5 substituents α ₁ described below), (xvi) amino group (may have 1 or 2 substituents α ₁ described below), or (xvii) hydroxyl,

The substituent moiety _α1 represents (i) C ₁ -C ₆ alkyl, (ii) C ₁ -C ₆ haloalkyl, (iii) C ₁ -C ₆ alkoxy, (iv) halogen atom, (v) Hydroxy, (vi) cyano, (vii) nitro, (viii) C ₃ -C ₁₀ cycloalkyl, (ix) C ₆ -C ₁₀ aryl (may have 1 to 5 substituents β below), (x) C ₇ -C ₁₆ aralkyl group (the aryl group may have 1-5 substituents β as described below), (xi) C ₁ -C ₇ aliphatic acyl group, (xii) C ₄ -C ₁₁ ring Alkylcarbonyl, (xiii) C ₇ -C ₁₁ arylcarbonyl (may have 1-5 following substituent moieties β), (xiv) C ₈ -C ₁₇ aralkylcarbonyl (may have 1-5 the following substituent moieties β), (xv) monocyclic heteroaryl ring carbonyl (may have 1 to 5 substituent moieties β below), (xvi) carbamoyl group, (xvii) C ₇ -C ₁₁ aryl Aminocarbonyl (may have 1-5 substituents β below on the aryl group), (xviii) amino (may have 1 or 2 substituents β below) or (xix) carboxyl,

The substituent moiety β represents (i) C ₁ -C ₁₀ alkyl group, (ii) halogen atom, (iii) C ₆ -C ₁₀ aryl group (may have 1-5 substituent moieties γ below), (iv) C ₇ -C ₁₆ aralkyl (the aryl may have 1-5 substituents γ as follows), (v) C ₁ -C ₇ aliphatic acyl, (vi) C ₇ -C ₁₁ arylcarbonyl (can Having 1-5 of the following substituents γ), (vii) C ₈ -C ₁₇ aralkylcarbonyl (the aryl may have 1-5 of the following substituting γ), (viii) C ₄ -C ₁₁ Cycloalkylcarbonyl, (ix) monocyclic type heteroaryl ring carbonyl (may have 1 to 5 substituent moieties γ described below), (x) carbamoyl or (xi) C ₇ -C ₁₁ arylaminocarbonyl ( On the aryl group, there may be 1-5 substituent moieties γ) described below,

The substituted moiety γ represents a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group, a halogen atom or a hydroxyl group].

Moreover, the Z ₂ O-group in the general formula (II), the Z ₃ S-group in the general formula (III) and the Z ₄ in the general formula (IV) are all included in the range of Z ₁ in the general formula (I) within.

In this application,

When R ₁ , R ₂ , R ₃ , R ₄ , X, Z ₁ , Z ₃ , α ₁ and γ represent "C ₁ -C ₆ alkyl", said group represents a group with 1-6 carbon atoms Straight chain or branched chain alkyl. Examples of such groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, sec-pentyl, isopentyl, 2-methyl Butyl, neopentyl, 1-ethylpropyl, hexyl, 4-methylpentyl (isohexyl), 3-methylpentyl, 2-methylpentyl, 1-methylpentyl (sec-hexyl ), 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl , 2,3-dimethylbutyl or 2-ethylbutyl. Preferred is C _{1 -C4} alkyl, more preferred is C ₁ -C ₂ alkyl.

When R ₁ , R ₂ , R ₃ , R ₄ , Z ₁ , Z ₃ and Z ₄ represent "C ₆ -C ₁₀ aryl (may have 1-5 substituents α ₁ )", X, α ₁ and α ₂ represents "C ₆ -C ₁₀ aryl (may have 1-5 substituents β below)", β represents "C ₆ -C ₁₀ aryl (may have 1-5 substituents γ below) ", when Z ₂ represents "C ₆ -C ₁₀ aryl (may have 1-5 substituents α ₂ )", examples of the C ₆ -C ₁₀ aryl moiety include phenyl, indenyl and naphthalene base.

When R ₁ , R ₂ , R ₃ , R ₄ , Z ₁ and Z ₃ represent "C ₇ -C ₁₆ aralkyl (the aryl group may have 1-5 substituents α ₁ as follows)", X, α ₁ and α ₂ represent "C ₇ -C ₁₆ aralkyl (the aryl may have 1-5 substituents β below)", and β represents "C ₇ -C ₁₆ aralkyl (on the aryl When there may be 1-5 of the following substituted moieties γ)", said C ₇ -C ₁₆ aralkyl moiety represents a C ₁ -C ₆ alkyl substituted by one of the above C ₆ -C ₁₀ aryl groups. Examples of the aralkyl moiety include benzyl, naphthylmethyl, indenylmethyl, 1-phenethyl, 2-phenethyl, 1-naphthylethyl, 2-naphthylethyl, 1-phenylpropyl , 2-phenylpropyl, 3-phenylpropyl, 1-naphthylpropyl, 2-naphthylpropyl, 3-naphthylpropyl, 1-phenylbutyl, 2-phenylbutyl, 3-phenylbutyl, 4 -Phenylbutyl, 1-naphthylbutyl, 2-naphthylbutyl, 3-naphthylbutyl, 4-naphthylbutyl, 5-phenylpentyl, 5-naphthylpentyl, 6-phenylhexyl and 6-naphthylhexyl .

When R ₁ , R ₂ and R ₃ represent a "C ₁ -C ₆ alkylsulfonyl group", said group represents a group formed by bonding the above C ₁ -C ₆ alkyl group to a sulfonyl group. Examples of such groups are methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, Pentylsulfonyl, isopentylsulfonyl, 2-methylbutylsulfonyl, neopentylsulfonyl, 1-ethylpropylsulfonyl, hexylsulfonyl, 4-methylpentylsulfonyl, 3- Methylpentylsulfonyl, 2-methylpentylsulfonyl, 3,3-dimethylbutylsulfonyl, 2,2-dimethylbutylsulfonyl, 1,1-dimethylbutylsulfonyl Acyl, 1,2-dimethylbutylsulfonyl, 1,3-dimethylbutylsulfonyl, 2,3-dimethylbutylsulfonyl and 2-ethylbutylsulfonyl. C ₁ -C ₄ alkylsulfonyl is preferred, C ₁ -C ₂ alkylsulfonyl is more preferred, methylsulfonyl is most preferred.

When R ₁ , R ₂ and R ₃ represent "C ₁ -C ₆ haloalkylsulfonyl", said group means that the alkyl part of the above C ₁ -C ₆ alkylsulfonyl is substituted by one or more halogen atoms group. Examples of such groups are trifluoromethylsulfonyl, trichloromethylsulfonyl, difluoromethylsulfonyl, dichloromethylsulfonyl, dibromomethylsulfonyl, fluoromethylsulfonyl, 2,2, 2-trifluoroethylsulfonyl, 2,2,2-trichloroethylsulfonyl, 2-bromoethylsulfonyl, 2-chloroethylsulfonyl, 2-fluoroethylsulfonyl, 2-iodoethyl methylsulfonyl, 3-chloropropylsulfonyl, 4-fluorobutylsulfonyl, 6-iodohexylsulfonyl and 2,2-dibromoethylsulfonyl. Preferred is C ₁ -C ₄ haloalkylsulfonyl, more preferably C ₁ -C ₂ haloalkylsulfonyl, most preferably trifluoromethylsulfonyl.

When R ₁ , R ₂ and R ₃ represent "C ₆ -C ₁₀ arylsulfonyl (may have 1-5 substituent moieties α ₁ ) below", the C ₆ -C ₁₀ arylsulfonyl moiety represents A group formed by bonding the above C ₆ -C ₁₀ aryl to a sulfonyl group. Examples of the C ₆ -C ₁₀ arylsulfonyl moiety are phenylsulfonyl, indenylsulfonyl and naphthylsulfonyl.

When R ₁ , R ₂ and R ₃ represent "C ₇ -C ₁₆ aralkylsulfonyl (the aryl group may have 1-5 substituents α ₁ below)", there is no C ₇ - The C ₁₆ aralkylsulfonyl moiety represents a group formed by bonding the above-mentioned C ₇ -C ₁₆ aralkyl to a sulfonyl group. Examples of the C ₇ -C ₁₆ aralkylsulfonyl moiety are phenylmethylsulfonyl, naphthylmethylsulfonyl, indenemethylsulfonyl, 1-phenethylsulfonyl, 2-phenethylsulfonyl, 1 -Naphthylethylsulfonyl, 2-naphthylethylsulfonyl, 1-phenylpropylsulfonyl, 2-phenylpropylsulfonyl, 3-phenylpropylsulfonyl, 1-naphthylpropylsulfonyl, 2-naphthalene Propylsulfonyl, 3-Naphthylpropylsulfonyl, 1-Phenylbutylsulfonyl, 2-Phenylbutylsulfonyl, 3-Phenylbutylsulfonyl, 4-Phenylbutylsulfonyl, 1-Naphthylbutylsulfonyl Sulfonyl, 2-naphthylbutylsulfonyl, 3-naphthylbutylsulfonyl, 4-naphthylbutylsulfonyl, 5-phenylpentylsulfonyl, 5-naphthylpentylsulfonyl, 6-phenylhexylsulfonyl and 6-Naphthylhexylsulfonyl.

When W ₁ and W ₂ represent "C ₁ -C ₈ alkylene", said group represents a linear or branched chain alkylene group having 1-8 carbon atoms, examples of which are methylene, methyl Methylene, ethylene, propylene, trimethylene, 1-methylethylene, tetramethylene, 1-methyltrimethylene, 2-methyltrimethylene, 3-methyltrimethylene Methyl, 1-methylpropylene, 1,1-dimethylethylene, pentamethylene, 1-methyltetramethylene, 2-methyltetramethylene, 3-methyltetramethylene Methylene, 4-methyltetramethylene, 1,1-dimethyltrimethylene, 2,2-dimethyltrimethylene, 3,3-dimethyltrimethylene, hexamethylene , 1-methylpentamethylene, 2-methylpentamethylene, 3-methylpentamethylene, 4-methylpentamethylene, 5-methylpentamethylene, 1,1- Dimethyltetramethylene, 2,2-dimethyltetramethylene, 3,3-dimethyltetramethylene, 4,4-dimethyltetramethylene, heptamethylene, 1 -Methylhexamethylene, 2-methylhexamethylene, 5-methylhexamethylene, 3-ethylpentamethylene, octamethylene, 2-methylheptamethylene, 5 -Methylheptamethylene, 2-ethylhexamethylene, 2-ethyl-3-methylpentamethylene and 3-ethyl-2-methylpentamethylene. It is preferably straight chain C ₁ -C ₆ alkylene, more preferably straight chain C ₁ -C ₄ alkylene, most preferably straight chain C ₁ -C ₂ alkylene.

When X, _α1 and γ represent "C ₁ -C ₆ haloalkyl", said group represents a group in which the above C ₁ -C ₆ alkyl is substituted by one or more halogen atoms. Examples of such groups are trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trifluoroethyl, 2,2,2 -Trichloroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, 2-iodoethyl, 3-chloropropyl, 4-fluorobutyl, 6-iodohexyl and 2,2 - dibromoethyl. It is preferably C ₁ -C ₄ haloalkyl, more preferably C ₁ -C ₂ haloalkyl, most preferably trifluoromethyl.

When X, Z ₁ , Z ₄ and α ₁ represent "C ₁ -C ₆ alkoxy", said group represents a group formed by bonding the above C ₁ -C ₆ alkyl group to an oxygen atom, examples of which are Methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, 2-methylbutyl Oxygen, neopentyloxy, 1-ethylpropoxy, hexyloxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 3,3-dimethyl 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy, 2 , 3-dimethylbutoxy and 2-ethylbutoxy. It is preferably C ₁ -C ₄ alkoxy, more preferably C ₁ -C ₂ alkoxy, most preferably methoxy.

When X, Z ₁ , Z ₄ , α ₁ , β and γ represent "halogen atom", examples of the group include fluorine atom, chlorine atom, bromine atom and iodine atom. A fluorine atom, a chlorine atom and a bromine atom are preferred, and a fluorine atom and a chlorine atom are more preferred.

When X, Z ₃ , α ₁ and α ₂ represent "C ₃ -C ₁₀ cycloalkyl", the group represents a 3-10 membered saturated cyclic hydrocarbon group, examples of which include cyclopropyl, cyclobutyl, cyclo Pentyl, cyclohexyl, cycloheptyl, norbornyl (norbornyl) and adamantyl (adamantyl; adamantyl). Preferred are cyclopropyl, cyclohexyl and adamantyl, more preferably adamantyl.

When X, α ₁ , α ₂ and β represent "C ₁ -C ₇ aliphatic acyl groups", examples of said groups include formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, isobutyryl, Valeryl, pivaloyl, hexanoyl, acryloyl, methacryloyl and crotonyl. C ₁ -C ₅ aliphatic acyl is preferred, C ₁ -C ₃ aliphatic acyl is more preferred, acetyl is most preferred.

When X, α ₁ , α ₂ and β represent "C ₄ -C ₁₁ cycloalkylcarbonyl", said group represents a group formed by bonding the above C ₃ -C ₁₀ cycloalkyl to a carbonyl group, examples of which are Cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl, norbornylcarbonyl and adamantylcarbonyl. Preference is given to C ₄ -C ₇ cycloalkylcarbonyl.

When X, Z ₂ , α ₁ and α ₂ represent "C ₇ -C ₁₁ arylcarbonyl (may have 1-5 substituents β below)", β represents "C ₇ -C ₁₁ aryl carbonyl (may have 1- When 5 of the following substituting moieties γ)", the C ₇ -C ₁₁ arylcarbonyl moiety represents a group formed by bonding the above C ₆ -C ₁₀ aryl to a carbonyl. Examples of the C ₇ -C ₁₁ arylcarbonyl moiety are benzoyl, 1-indancarbonyl, 2-indancarbonyl and 1- or 2-naphthoyl.

When X, α ₁ and α ₂ represent "C ₈ -C ₁₇ aralkylcarbonyl (the aryl group may have 1-5 substituents β below)", β represents "C ₈ -C ₁₇ aralkylcarbonyl (the aryl group may have 1-5 substituting moieties γ below)", the C ₈ -C ₁₇ aralkylcarbonyl moiety represents the group formed by the above C ₇ -C ₁₆ aralkyl group being bonded to a carbonyl group . Examples of the C ₈ -C ₁₇ aralkylcarbonyl moiety are phenylacetyl, 3-phenylpropionyl, 4-phenylbutyryl, 5-phenylpentanoyl, 6-phenylhexanoyl, naphthylacetyl 4-naphthylbutyryl and 6-naphthylhexanoyl.

When X, α ₁ and α ₂ represent "heteroaromatic carbonyl of monocyclic type (may have 1-5 following substituting moieties β)", β represents "heteroaromatic carbonyl of monocyclic type (may have 1-5 When the following substituent moiety γ)", the monocyclic heteroaryl ring carbonyl moiety means that a 5-7 membered heteroaryl ring having 1-3 heteroatoms selected from oxygen atom, nitrogen atom and sulfur atom is bonded to A group formed on a carbonyl. Examples of the heteroaryl carbonyl moiety of the monocyclic type include furylcarbonyl, thienylcarbonyl, pyrrolylcarbonyl, pyrazolylcarbonyl, imidazolylcarbonyl, oxazolylcarbonyl, isoxazolylcarbonyl, thiazolylcarbonyl, iso Thiazolylcarbonyl, 1,2,3-oxadiazolylcarbonyl, triazolylcarbonyl and thiadiazolylcarbonyl and other 5-membered heteroaromatic ring carbonyl, pyranylcarbonyl, nicotinoyl, isonicotinoyl, pyridazinylcarbonyl 6-membered heteroaromatic ring carbonyls such as , pyrimidinylcarbonyl and pyrazinylcarbonyl, and 7-membered heteroaryl ring carbonyls such as aza-carbonyl.

When X, α ₁ and α ₂ represent "C ₇ -C ₁₁ arylaminocarbonyl (the aryl may have 1-5 substituents β as follows)", β represents "C ₇ -C ₁₁ arylaminocarbonyl (the aryl group may have 1-5 substituent moieties γ below)", the C ₇ -C ₁₁ arylaminocarbonyl moiety represents a group in which the amino group of the aminocarbonyl group is substituted by the above C ₆ -C ₁₀ aryl group group. Examples of the C ₇ -C ₁₁ arylaminocarbonyl moiety are phenylaminocarbonyl, indenylaminocarbonyl and naphthylaminocarbonyl.

When Z ₁ and Z ₄ represent "C ₁ -C ₆ alkylthio group", it means a group formed by binding the above C ₁ -C ₆ alkyl group to a sulfur atom. Examples of such groups are methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio , 2-methylbutylthio, neopentylthio, 1-ethylpropylthio, hexylthio, 4-methylpentylthio, 3-methylpentylthio, 2-methylpentylthio, 3,3-dimethylbutylthio, 2,2-dimethylbutylthio, 1,1-dimethylbutylthio, 1,2-dimethylbutylthio, 1,3-dimethyl butylthio, 2,3-dimethylbutylthio and 2-ethylbutylthio. It is preferably C ₁ -C ₄ alkylthio, more preferably C ₁ -C ₂ alkylthio, most preferably methylthio.

When Z ₁ and Z ₄ represent "C ₆ -C ₁₀ aryloxy (may have 1-5 substituents α ₁ )", the C ₆ -C ₁₀ aryloxy moiety represents the above C ₆ -C ₁₀ A group formed by substituting an aryl group with an oxygen atom. Examples of the C ₆ -C ₁₀ aryloxy moiety are phenoxy, indenyloxy and naphthyloxy.

When Z ₁ and Z ₄ represent "C ₇ -C ₁₆ aralkyloxy (the aryl group may have 1-5 substituents α ₁ as follows)", the C ₇ -C ₁₆ aralkoxy moiety Represents a group formed by substituting the above C ₇ -C ₁₆ aralkyloxy group with an oxygen atom. Examples of the C ₇ -C ₁₆ aralkyloxy group include benzyloxy, naphthylmethoxy, indenemethoxy, 1-phenylethoxy, 2-phenylethoxy, 1-naphthaleneethoxy, 2- Naphthaleneethoxy, 1-phenylpropoxy, 2-phenylpropoxy, 3-phenylpropoxy, 1-naphthylpropoxy, 2-naphthylpropoxy, 3-naphthylpropoxy, 1-benzene Butoxy, 2-phenylbutoxy, 3-phenylbutoxy, 4-phenylbutoxy, 1-naphthylbutoxy, 2-naphthylbutoxy, 3-naphthylbutoxy, 4-naphthylbutoxy Oxygen, 5-Phenylpentyloxy, 5-Naphthylpentyloxy, 6-Phenylhexyloxy and 6-Naphthylhexyloxy.

When Z ₁ and Z ₄ represent "C ₃ -C ₁₀ cycloalkoxy", said group represents a group in which the above C ₃ -C ₁₀ cycloalkyl is substituted with an oxygen atom. Examples of such groups are cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, cycloheptyloxy, norbornyloxy and adamantyloxy. It is preferably C ₃ -C ₆ cycloalkoxy, more preferably C ₅ -C ₆ cycloalkoxy.

When Z ₁ and Z ₄ represent "C ₃ -C ₁₀ cycloalkylthio group", said group represents a group formed by replacing the above C ₃ -C ₁₀ cycloalkyl group with a sulfur atom. Examples of such groups are cyclopropylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, cycloheptylthio, norbornylthio and adamantylthio. It is preferably a C ₃ -C ₆ cycloalkylthio group, more preferably a C ₅ -C ₆ cycloalkylthio group.

When Z ₂ and Z ₃ represent "a saturated heterocyclic group (may have 1-5 substituent moieties α ₁ ) described below", the saturated heterocyclic moiety represents 4 having at least one nitrogen atom, oxygen atom or sulfur atom -7-membered saturated heterocyclic group. Examples of the saturated heterocyclic moiety include 4-membered saturated heterocyclic rings such as azetidyloxy, pyrrolidinyl, tetrahydrofuryl, tetrahydrothiophenyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, 5-membered saturated heterocycles such as isothiazolidinyl, piperidino, tetrahydropyranyl, tetrahydrothiopyranyl, piperazino (piperazino; piperazino), morpholino, thiomorpholino and other 6-membered A saturated heterocycle, and a 7-membered saturated heterocycle such as a homopiperazino group (Homopiperazino; homopiperazino).

When Z ₁ and Z ₄ represent "saturated heterocyclic oxy group (may have 1-5 substituent moieties α ₁ ) below", the saturated heterocyclic oxy group moiety means that the above-mentioned saturated heterocyclic ring is bound to an oxygen atom to form group. Examples of the saturated heterocyclic epoxy moiety include 4-membered saturated heterocyclic epoxy groups such as azetidyloxy, pyrrolidinyloxy, tetrahydrofuryloxy, tetrahydrothiopheneoxy, imidazolidinyloxy, oxazolidinyloxy, iso Oxazolidinyloxy, thiazolidinyloxy, isothiazolyloxy and other 5-membered saturated heterocyclic epoxy groups, piperidinooxy, tetrahydropyranyloxy, tetrahydrothiopyranyloxy, piperazino 6-membered saturated heterooxyl groups such as oxy (piperazinooxy; piperazinoxy), morpholinooxy, and thiomorpholinooxy; and 7-membered homopiperazinooxy (homopiperazinooxy; homopiperazinoxy) Saturated Heterocyclic Oxygen.

When Z ₁ and Z ₃ represent "monocyclic type heteroaryl epoxy group (may have 1-5 substituent moieties α ₁ ) below", the monocyclic type heteroaryl epoxy group part means having 1- A group formed by bonding three 5- to 7-membered heteroaryl rings of heteroatoms selected from oxygen atom, nitrogen atom and sulfur atom to an oxygen atom. Examples of the heteroaryl epoxy moiety of the monocyclic type include furyloxy, thienyloxy, pyrroleoxy, pyrazolyloxy, imidazolyloxy, oxazolyloxy, isoxazolyloxy, thiazolyloxy, Isothiazolyloxy, 1,2,3-oxadiazolyloxy, triazolyloxy, tetrazolyloxy, thiadiazolyloxy and other 5-membered heteroaryl epoxy groups, pyranyloxy, pyridyloxy, 6-membered heteroaryl epoxy groups such as pyridazinyloxy, pyrimidinyloxy, and pyrazinyloxy, and 7-membered heteroaryloxyl groups such as aza-yloxy.

When Z ₁ and Z ₄ represent "C ₆ -C ₁₀ arylthio (may have 1-5 substituents α ₁ ) below", the C ₆ -C ₁₀ arylthio moiety represents the above C ₆ -C ₁₀ A group formed by substituting an aryl group with a sulfur atom. Examples of the C ₆ -C ₁₀ arylthio moiety are phenylthio, indenylthio and naphthylthio.

When Z ₁ and Z ₄ represent "C ₇ -C ₁₆ aralkylthio group (the aryl group may have 1-5 substituents α ₁ as follows)", the C ₇ -C ₁₆ aralkylthio group moiety Represents a group formed by replacing the above-mentioned C ₇ -C ₁₆ aralkyl group with a sulfur atom. Examples of the C ₇ -C ₁₆ aralkylthio moiety are benzylthio, naphthylmethylthio, indenylthio, 1-phenethylthio, 2-phenethylthio, 1-naphthylethylthio, 2- -Naphthylethylthio, 1-phenylpropylthio, 2-phenylpropylthio, 3-phenylpropylthio, 1-naphthylpropylthio, 2-naphthylpropylthio, 3-naphthylpropylthio, 1- Phenylbutylthio, 2-Phenylbutylthio, 3-Phenylbutylthio, 4-Phenylbutylthio, 1-Naphthylbutylthio, 2-Naphthylbutylthio, 3-Naphthylbutylthio, 4-Naphthalene Butylthio, 5-phenylpentylthio, 5-naphthylpentylthio, 6-phenylhexylthio and 6-naphthylhexylthio.

When Z ₁ and Z ₄ represent "saturated heterocyclic thio group (may have 1-5 substituents α ₁ )", the saturated heterocyclic thio group represents the above-mentioned saturated heterocycle bonded to the sulfur atom formed group. Examples of the saturated heterocyclic thio moiety include 4-membered saturated heterocyclic thio groups such as azetidylthio, pyrrolidinylthio, tetrahydrofurylthio, imidazolidinylthio, oxazolidinyloxy, iso 5-membered saturated heterocyclic thio groups such as oxazolidinylthio, thiazolidinylthio, and isothiazolylthio, piperidinylthio, tetrahydropyranylthio, tetrahydrothiopyranylthio, 6-membered saturated heterocyclic thio groups such as piperazinylthio, morpholinothio (molhoriruチオ; morpholylthio), thiomorpholinothio (チオモルリルチオ; thiomorpholylthio), and homopiperazinothiol ( 7-membered saturated heterocyclic thio group such as ホモピペラジノチオ; homopiperazinothio).

When Z ₁ and Z ₄ represent "monocyclic type heteroaryl ring thio group (may have 1-5 following substituent moieties α ₁ )", said monocyclic type heteroaryl ring thio group has 1- A group formed by bonding a 5-7 membered heteroaromatic ring of three heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom to a sulfur atom. Examples of heteroaryl thio moieties of the monocyclic type are furylthio, thienylthio, pyrrolylthio, pyrazolylthio, imidazolylthio, oxazolylthio, isoxazolyl Sulfuryl, thiazolylthio, isothiazolylthio, 1,2,3-oxadiazolylthio, triazolylthio, tetrazolylthio, thiadiazolylthio and other 5-membered heteroaryls Cyclothio, pyrylthio, pyridylthio, pyridazinylthio, pyrimidinylthio, pyrazinylthio and other 6-membered heteroaromatic ringthio groups, and aza-ylthio and other 7-membered Heteroaryl ring sulfur group.

When the substituent moiety β represents "C ₁ -C ₁₀ alkyl", said group represents a straight chain or branched chain alkyl group having 1 to 10 carbon atoms, examples of which are defined above for C ₁ -C ₆ In addition to the examples given for the alkyl group, heptyl, 1-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1-propylbutyl , 4,4-dimethylpentyl, octyl, 1-methylheptyl, 2-methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl, 6 -Methylheptyl, 1-propylpentyl, 2-ethylhexyl, 5,5-dimethylhexyl, nonyl, 3-methyloctyl, 4-methyloctyl, 5-methyloctyl Base, 6-methyloctyl, 1-propylhexyl, 2-ethylheptyl, 6,6-dimethylheptyl, decyl, 1-methylnonyl, 3-methylnonyl, 8 -Methylnonyl, 3-ethyloctyl, 3,7-dimethyloctyl and 7,7-dimethyloctyl, preferably C ₁ -C ₆ alkyl, more preferably C ₁ -C ₄ alkane radical, most preferably C ₁ -C ₂ alkyl.

According to the definition of the substituting moiety γ above,

When the substituent moiety β represents "C ₆ -C ₁₀ aryl (may have 1-5 substituent moieties γ)", examples of the group having the substituent moiety γ are 4-methylphenyl, 4-methyl Naphthyl, 3,4-dimethylphenyl, 2,3,4-trimethylphenyl, 4-propylphenyl, 4-propylnaphthyl, 2-, 3- or 4-trifluoromethyl phenyl, 2-, 3- or 4-trifluoromethylnaphthyl, 3,4-ditrifluoromethylphenyl, 2,3,4-tritrifluoromethylphenyl, 4-tetrafluoropropane phenyl, 4-tetrafluoropropylnaphthyl, 4-fluorophenyl, 4-fluoronaphthyl, 3,4-difluorophenyl, 2,3,4-trifluorophenyl, 4-hydroxyphenyl , 4-hydroxynaphthyl, 3,4-dihydroxyphenyl and 2,3,4-trihydroxyphenyl. Preferably the group is C ₆ -C ₁₀ aryl (may have 1-3 substituted moieties γ), more preferably phenyl (may have 1-3 substituted moieties γ), more preferably phenyl (may have 1 substituted moiety Moiety γ), most preferably phenyl or 4-trifluoromethylphenyl.

When the substituent moiety β represents "C ₇ -C ₁₆ aralkyl group (may have 1-5 substituent moieties γ on the aryl group)", examples of the group having the substituent moiety include 4-methylbenzyl, 2 , 3,4-trimethylbenzyl, 4-methylphenethyl, 2,3,4-trimethylphenethyl, 4-(4-methylphenyl)butyl, 2-, 3- Or 4-trifluoromethylbenzyl, 3,4-ditrifluoromethylbenzyl, 2,3,4-tritrifluoromethylbenzyl, 4-tetrafluoropropylbenzyl, 4-trifluoromethylbenzyl phenylethyl, 3,4-ditrifluoromethylphenethyl, 2,3,4-tritrifluoromethylphenethyl, 4-tetrafluoropropylphenethyl, 4-(4-trifluoromethylphenethyl Methylphenyl) butyl, 4-(4-tetrafluoropropyl) butyl, 6-(4-trifluoromethylphenyl) hexyl, 6-(4-tetrafluoropropylphenyl) hexyl, 2 -, 3- or 4-trifluoromethylnaphthylmethyl, 4-tetrafluoropropylnaphthylmethyl, 4-(4-trifluoromethylnaphthyl)butyl, 4-(4-tetrafluoropropyl Naphthyl) butyl, 4-fluorobenzyl, 2,3,4-trifluorobenzyl, 4-fluorophenethyl, 2,3,4-trifluorophenethyl, 4-(4-fluorobenzene base) butyl, 4-hydroxybenzyl, 2,3,4-trihydroxybenzyl, 4-hydroxyphenethyl, 2,3,4-trihydroxyphenethyl and 4-(4-hydroxyphenyl) butyl. Preferably, the group is a C ₇ -C ₁₆ aralkyl group (the aryl group may have 1-3 substituents γ), more preferably a phenyl C ₁ -C ₆ alkyl group (the phenyl group may have 1- 3 substituted moieties γ), more preferably phenyl C ₁ -C ₆ alkyl (1-3 substituted moieties γ on phenyl), more preferably phenyl C ₁ -C ₆ alkyl (on phenyl may have 1 trifluoromethyl group as a substituent), most preferably phenyl C ₁ -C ₂ alkyl (may have 1 trifluoromethyl group as a substituent on phenyl).

When the substituted moiety β represents "C ₇ -C ₁₁ arylcarbonyl (may have 1-5 substituted moieties γ)", examples of the group having the substituted moiety include 4-methylbenzoyl, 1- or 2- (5-Methyl)naphthoyl, 4-trifluoromethylbenzoyl, 4-tetrafluoropropylbenzoyl, 1-(5-trifluoromethylindan)carbonyl, 2-(5-trifluoromethylbenzoyl) Fluoromethylindane) carbonyl, 2-(6-trifluoromethylindane) carbonyl, 1- or 2-(5-trifluoromethyl) naphthoyl, 4-fluorobenzoyl, 1- or 2 -(5-fluoro)naphthoyl, 4-hydroxybenzoyl and 1- or 2-(5-hydroxy)naphthoyl. Preferably the group is C ₇ -C ₁₁ arylcarbonyl (may have 1-3 substituted moieties γ), more preferably benzoyl (may have 1-3 substituted moieties γ), more preferably benzoyl (may have 1-3 substituted moieties γ), more preferably benzoyl (can have having 1 substituting moiety γ), most preferably benzoyl (may have 1 trifluoromethyl group as substituting moiety).

When the substituent moiety β represents "C ₈ -C ₁₇ aralkylcarbonyl (1-5 substituent moieties γ may be present on the aryl group", examples of the group having the substituent moiety are 4-methylphenylacetyl , 4-(4-methyl)phenylbutyryl, 6-(methylnaphthyl)hexanoyl, 2-, 3- or 4-trifluoromethylphenylacetyl, 4-tetrafluoropropylphenyl Acetyl, 4-(4-trifluoromethyl)phenylbutyryl, 6-(4-trifluoromethyl)phenylhexanoyl, 4-trifluoromethylnaphthylacetyl, 6-(trifluoromethyl) Nylnaphthyl)hexanoyl, 4-fluorophenylacetyl, 4-(4-fluoro)phenylbutyryl, 6-(fluoronaphthyl)hexanoyl, 4-hydroxyphenylacetyl, 4-(4- Hydroxy) phenylbutyryl and 6-(hydroxynaphthyl) hexanoyl. Preferably said group is C ₈ -C ₁₇ aralkylcarbonyl (can have 1-3 substituents γ on aryl), more preferably is phenyl C ₁ -C ₆ alkylcarbonyl (the aryl can have 1-3 substituents γ), more preferably phenyl C ₁ -C ₆ alkylcarbonyl (the aryl can have 1 C ₁ -C ₆ haloalkyl as a substituent), more preferably phenyl C ₁ -C ₆ alkylcarbonyl (the aryl may have 1 trifluoromethyl as a substituent), most preferably phenylacetyl or 4-trifluoromethyl Phenylacetyl.

When the substituent moiety β represents "monocyclic type heteroaromatic carbonyl group (may have 1 to 5 substituent moieties γ)", examples of the group having the substituent moiety include methylfurylcarbonyl, methylthienylcarbonyl, Methylpyrrolylcarbonyl, Methylnicotinoyl, Trifluoromethylfurylcarbonyl, Trifluoromethylthienylcarbonyl, Trifluoromethylpyrrolylcarbonyl, Trifluoromethyloxazolylcarbonyl, Trifluoromethylthiazolyl Carbonyl, trifluoromethylnicotinoyl, tetrafluoropropylfurylcarbonyl, tetrafluoropropylthienylcarbonyl, tetrafluoropropylpyrrolylcarbonyl, fluorofurylcarbonyl, fluorothienylcarbonyl, fluoropyrrolylcarbonyl , fluoronicotinoyl, hydroxyfurylcarbonyl, hydroxythienylcarbonyl, hydroxypyrrolylcarbonyl and hydroxynicotinoyl. Preferably, the group is a monocyclic heteroaryl ring carbonyl (may have 1-3 substituted moieties γ), more preferably a monocyclic heteroaryl ring carbonyl group (may have 1 substituted moiety γ), and more preferably a monocyclic heteroaryl ring carbonyl group (may have 1 substituted moiety γ). Ring-type heteroaryl ring carbonyl (may have 1 trifluoromethyl group as a substituting part), more preferably 5- or 6-membered monocyclic heteroaryl ring carbonyl (may have 1 trifluoromethyl group as a substituting part), most Preference is given to furylcarbonyl, thienylcarbonyl, pyrrolylcarbonyl or nicotinoyl.

When the substituent moiety β represents "C ₇ -C ₁₁ arylaminocarbonyl (may have 1 to 5 substituent moieties γ on the aryl group)", an example of the group having the substituent moiety is 4-methylphenyl Carbamoyl, 2,3,4-trimethylphenylcarbamoyl, 1- or 2-(6- or 7-methylnaphthyl)carbamoyl, 2-, 3- or 4-trifluoromethyl phenylcarbamoyl, 4-tetrafluoropropylphenylcarbamoyl, 3,4-difluoromethylphenylcarbamoyl, 2,3,4-trifluoromethylphenylcarbamoyl, 1- or 2-(6- or 7-trifluoromethylnaphthyl)carbamoyl, 2-(6-tetrafluoropropylnaphthyl)carbamoyl, 4-fluorophenylcarbamoyl, 2,3 , 4-trifluorophenylcarbamoyl, 1- or 2-(6- or 7-fluoronaphthyl)carbamoyl, 4-hydroxyphenylcarbamoyl, 2,3,4-trihydroxyphenylamino Formyl and 1- or 2-(6- or 7-hydroxynaphthyl)carbamoyl. Preferably the group is C ₇ -C ₁₁ arylaminocarbonyl (can have 1-3 substituents γ on aryl), more preferably phenylaminocarbonyl (can have 1-3 substituted moieties on phenyl γ), more preferably phenylaminocarbonyl (can have 1-3 C ₁ -C ₆ haloalkyl groups as substituent γ on the phenyl group), most preferably phenylaminocarbonyl (can have 1 trifluoromethyl as substituted part).

According to the definition of β above,

When X, α ₁ and α ₂ represent "C ₆ -C ₁₀ aryl (may have 1-5 substituted moieties β)", examples of the group having substituted moieties are methylphenyl, acetylphenyl , benzoylphenyl, biphenyl, methylbiphenyl, methylnaphthyl, acetylnaphthyl and benzoylnaphthyl. Preferably said group is C ₆ -C ₁₀ aryl (may have 1-3 substituted moieties β), more preferably phenyl (may have 1-3 substituted moieties β), more preferably phenyl (may have 1 or 2 substituted moieties β), most preferably phenyl (may have 1 substituted moiety β).

When X, α ₁ and α ₂ represent "C ₇ -C ₁₆ aralkyl (1-5 substituted moieties β on the aryl group)", examples of the group with substituted moieties are methyl benzyl radical, acetylbenzyl, benzoylbenzyl, biphenylmethyl, methylbiphenylmethyl, methylnaphthylmethyl, acetylnaphthylmethyl, benzoylnaphthylmethyl , methylphenethyl, acetylphenethyl, methylnaphthylethyl, acetylnaphthylethyl, methylphenylbutyl, acetylphenylbutyl, methylnaphthylbutyl and acetyl Naphthylbutyl. Preferably the group is a C ₇ -C ₁₆ aralkyl group (can have 1-3 substituting moieties β on the aryl group, more preferably a phenyl C ₁ -C ₆ alkyl group (can have 1-3 substituting moieties on the aryl group) substituting moiety β), more preferably phenyl C ₁ -C ₄ alkyl (can have 1 or 2 substituting moieties β on aryl), most preferably benzyl or phenethyl (may have 1 substituting moiety β ).

When X, α ₁ and α ₂ represent "C ₇ -C ₁₁ aryl carbonyl (may have 1-5 substituent moieties β)", examples of the group having substituted moieties are methylbenzoyl, biphenyl Carbonyl, acetylbenzoyl, carbamoylbenzoyl, 4-trifluoromethylphenylcarbamoylbenzoyl and trifluoronaphthylcarbonyl. Preferably said group is C ₇ -C ₁₁ arylcarbonyl (may have 1-3 substituted moieties β), more preferably benzoyl (may have 1-3 substituted moieties β), more preferably benzoyl (may have 1 or 2 substituted moieties β), most preferably benzoyl (may have 1 substituted moiety β).

When X, α ₁ and α ₂ represent "C ₈ -C ₁₇ aralkylcarbonyl (the aryl group may have 1-5 substituting moieties β)", examples of the group having substituted moieties include methylbenzene Acyl acetyl, acetyl phenyl acetyl, benzoyl phenyl acetyl, biphenyl acetyl, carbamoyl phenyl acetyl, (4-trifluoromethylphenyl carbamoyl) phenyl acetyl , 4-(methylphenyl)butyryl, 4-[(4-trifluoromethylphenylcarbamoyl)phenyl]butyryl, methylnaphthylacetyl and carbamoylnaphthylacetyl. Preferably the gene is a C ₈ -C ₁₇ aralkylcarbonyl group (which may have 1-3 substituent moieties β on the aryl), more preferably a phenyl C ₂ -C ₇ alkylcarbonyl group (which may have 1-3 substituent moieties on the phenyl substituting moiety β), more preferably phenyl C ₂ -C ₇ alkylcarbonyl (may have 1 substituting moiety β on phenyl), most preferably phenylacetyl (may have 1 substituting moiety β on phenyl) .

When X, α ₁ and α ₂ represent "heteroaromatic ring carbonyl of monocyclic type (may have 1-5 substituent moieties β)", examples of the group having substituted moieties include methyl furyl carbonyl, methyl Thienylcarbonyl, methylpyrrolylcarbonyl, methyloxazolylcarbonyl, methylthiazolylcarbonyl, methyltriazolylcarbonyl, methylpyranylcarbonyl, methylnicotinoyl, methylpyridazinylcarbonyl, methyl Pyrimidinylcarbonyl, Acetylfurylcarbonyl, Acetylthienylcarbonyl, Acetylpyrrolylcarbonyl, Acetyloxazolylcarbonyl, Acetylthiazolylcarbonyl, Acetylnicotinoyl, Carbamoylfurylcarbonyl, Aminomethyl Acylthienylcarbonyl, carbamoylpyrrolylcarbonyl, carbamoyloxazolylcarbonyl, carbamoylthiazolylcarbonyl and carbamoylnicotinoyl. Preferably, the group is a monocyclic heteroaryl ring carbonyl (may have 1-3 substituted moieties β), more preferably a monocyclic heteroaryl ring carbonyl group (may have 1 or 2 substituted moieties β), even more A 5- or 6-membered monocyclic type heteroaryl ring carbonyl (may have 1 or 2 substituent moieties β) is preferred, and a 5- or 6-membered monocyclic type heteroaryl ring carbonyl group (may have 1 substituent moiety β) is most preferred.

When X, α ₁ and α ₂ represent "C ₇ -C ₁₁ arylaminocarbonyl (the aryl can have 1-5 substituent moieties β)", examples of the group with substituted moieties are methylbenzene ylcarbamoyl, biphenylcarbamoyl, acetylphenylcarbamoyl, methylnaphthylcarbamoyl and acetylnaphthylcarbamoyl. Preferably the group is C ₇ -C ₁₁ arylaminocarbonyl (which may have 1-3 substituent moieties β on aryl), more preferably phenylaminocarbonyl (which may have 1-3 substituent moieties on phenyl β), most preferably phenylaminocarbonyl (may have 1 substituent moiety β on phenyl).

When X and _α1 represent "an amino group that may have 1 or 2 substituent moieties β", examples of the group include amino, methylamino, ethylamino, propylamino, isopropylamino, butylamino, sec-butylamino, tert-butylamino, pentylamino, hexylamino, dimethylamino, diethylamino, N-ethyl-N-methylamino, dipropylamino, dibutylamino, dipentylamino, dihexylamino, Phenylamino, 1- or 2-indenylamino, 1- or 2-naphthylamino, benzylamino, 1- or 2-naphthylmethylamino, 1-indenylmethylamino, 1- or 2-phenylethyl phenylamino, 1-, 2- or 3-phenylpropylamino, 4-phenylbutylamino, 1-phenylbutylamino, 5-phenylpentylamino, 6-phenylhexylamino, dibenzylamino, methyl Acylamino, Acetylamino, Propionylamino, Butyrylamino, Isobutyrylamino, Valerylamino, Isovalerylamino, Pivaloylamino, Hexanoylamino, Acryloylamino, Methacryloylamino, Crotonyl Amino, benzoylamino, 1-indanecarbonylamino, 1- or 2-naphthoylamino, 1-indanecarbonylamino, 1- or 2-naphthoylamino, phenylacetylamino, 3-benzene Propionylamino, 4-phenylbutyrylamino, 5-phenylpentanoylamino, 6-phenylhexanoylamino, cyclopropionylamino, cyclobutyrylamino, cyclopentanoylamino, cyclohexanoylamino, pyrrole ylcarbonylamino, imidazolylcarbonylamino, pyrazolylcarbonylamino, triazolylcarbonylamino, tetrazolylcarbonylamino, nicotinylamino, isonicotinoylamino, pyrazinylcarbonylamino, pyrimidinylcarbonylamino, pyridazinyl Carbonylamino, thiazolylcarbonylamino, oxazolylcarbonylamino, oxadiazolylcarbonylamino, thiadiazolylcarbonylamino, N,N-diacetylamino, N-formyl-N-hexylamino, N-acetyl Base-N-methylamino, N-acetyl-N-ethylamino, N-acetyl-N-propylamino, N-acetyl-N-butylamino, N-acetyl-N-pentyl Amino, N-acetyl-N-hexylamino, N-benzoyl-N-methylamino, N-benzoyl-N-ethylamino, N-benzoyl-N-propylamino, N- Benzoyl-N-butylamino, N-benzoyl-N-pentylamino, N-benzoyl-N-hexylamino, N-benzoyl-N-phenylamino, N-benzyl -N-benzoylamino, N-hexyl-N-1-naphthoylamino, N-hexyl-N-2-naphthoylamino, N-hexyl-N-phenylacetylamino, N-isobutyl Base-N-cycloheptanoylamino, N-butyl-N-nicotinoylamino, N-hexyl-N-nicotinoylamino, N-isonicotinyl-N-hexylamino and 4-trifluoromethylphenylamino Formylamino. Preferably, the group can have 1-2 selected from C ₁ -C ₁₀ alkyl, C ₁ -C ₇ aliphatic acyl and phenylaminocarbonyl (the phenyl group can have 1-3 substituted moieties γ) The amino group of the substituted moiety, more preferably can have 1-2 selected from C ₁ -C ₆ alkyl, C ₁ -C ₂ aliphatic acyl and phenylaminocarbonyl (the phenyl can have 1 substituted moiety γ ) is most preferably an amino group which may have one phenylaminocarbonyl group (which may have one substituent γ on the phenyl group) as a substituent.

According to the definitions of X, _α1 and _α2 above,

When R ₁ , R ₂ , R ₃ , R ₄ , Z ₁ , Z ₃ and Z ₄ represent "C ₆ -C ₁₀ aryl (may have 1-5 substituent moieties α ₁ )", the substituted moiety Examples of radicals are methylphenyl, trifluoromethylphenyl, hydroxyphenyl, 4-hydroxy-2,3,5-trimethylphenyl, 3,5-di-tert-butyl-4-hydroxyphenyl phenyl, adamantylphenyl, 4-amino-3,5-dimethylphenyl, acetylphenyl, methoxyphenyl, benzoylphenyl, fluorophenyl, difluorophenyl, chlorophenyl , dichlorophenyl, bromophenyl, nitrophenyl, (dimethylamino)phenyl, biphenyl, methylbiphenyl, methylnaphthyl, trifluoronaphthyl, hydroxynaphthyl, methoxy Naphthyl, fluoronaphthyl and chloronaphthyl. Preferably the group is C ₆ -C ₁₀ aryl (may have 1-3 substituents α ₁ ), more preferably phenyl (may have 1-3 substituents α ₁ ), more preferably phenyl (may have 1 or 2 substituted moieties α ₁ ), most preferably phenyl (may have 1 substituted moiety α ₁ ).

When Z ₂ represents "C ₆ -C ₁₀ aryl (having 1-5 substituent moieties α ₂ )", examples of said group are adamantylphenyl, biphenyl, methylbiphenyl, benzyl Phenyl, acetylphenyl, cyclohexylcarbonylphenyl, benzoylphenyl, benzylcarbonylphenyl, pyridinecarbonylphenyl and phenylaminocarbonyl. Preferably the group is a C ₆ -C ₁₀ aryl group (with 1-3 substituted moieties α ₂ ), more preferably a phenyl group (with 1-3 substituted moieties α ₂ ), even more preferably a phenyl group (with 1 or 2 substituted moiety α ₂ ), most preferably phenyl (with 1 substituted moiety α ₂ ).

When R ₁ , R ₂ , R ₃ , R ₄ , Z ₁ , Z ₃ and Z ₄ represent "C ₇ -C ₁₆ aralkyl (the aryl group may have 1-5 substituents α ₁ )", Examples of such groups with substituted moieties are methylbenzyl, trifluoromethylbenzyl, hydroxybenzyl, 4-hydroxy-2,3,5-trimethylbenzyl, 3,5-di-tert-butyl Base-4-hydroxybenzyl, adamantylbenzyl, 4-amino-3,5-dimethylbenzyl, acetylbenzyl, methoxybenzyl, benzoylbenzyl, fluorobenzyl, difluorobenzyl Benzyl, chlorobenzyl, dichlorobenzyl, nitrobenzyl, (dimethylamino)benzyl, biphenylmethyl, methylbiphenylmethyl, methylphenethyl, trifluoromethyl Phenylethyl, hydroxyphenethyl, 4-hydroxy-2,3,5-trimethylphenethyl, 3,5-di-tert-butyl-4-hydroxyphenethyl, adamantylphenethyl, 4- Amino-3,5-dimethylphenethyl, acetylphenethyl, methoxyphenethyl, benzoylphenethyl, fluorophenethyl, difluorophenethyl, chlorophenethyl, nitrate phenylethyl, (dimethylamino)phenethyl, biphenylethyl, methylbiphenylethyl, methylphenylbutyl, trifluoromethylphenylbutyl, hydroxyphenylbutyl , 4-hydroxy-2,3,5-trimethylphenylbutyl, 3,5-di-tert-butyl-4-hydroxyphenylbutyl, adamantylphenylbutyl, 4-amino-3,5 -Dimethylphenylbutyl, acetylphenylbutyl, methoxyphenylbutyl, fluorophenylbutyl, chlorophenylbutyl, nitrophenylbutyl, (dimethylamino)benzene butyl, biphenylbutyl, methylnaphthylmethyl, trifluoronaphthylmethyl, hydroxynaphthylmethyl, methoxynaphthylmethyl, fluoronaphthylmethyl and chloronaphthylmethyl. Preferably, the group is a C ₇ -C ₁₆ aralkyl group (the aryl group may have 1-3 substituent moieties α ₁ ), more preferably a phenyl C ₁ -C ₆ alkyl group (the aryl group may have 1- 3 substituted moieties α ₁ ), more preferably phenyl C ₁ -C ₆ alkyl (can have 1 substituted moiety α ₁ on phenyl), more preferably phenyl C ₁ -C ₄ alkyl (on phenyl may have 1 substituent moiety α ₁ ), most preferably phenyl C ₁ -C ₂ alkyl (may have 1 substituent moiety α ₁ on phenyl).

When R ₁ , R ₂ and R ₃ represent "C ₆ -C ₁₀ arylsulfonyl group (may have 1-5 substituent moieties α ₁ )", examples of said groups having substituted moieties are methylphenyl Sulfonyl, acetylphenylsulfonyl, benzoylphenylsulfonyl, biphenylsulfonyl, methylbiphenylsulfonyl, methylnaphthylsulfonyl, acetylnaphthylsulfonyl, and benzoylnaphthalene Sulfonyl. Preferably the group is a C ₆ -C ₁₀ arylsulfonyl group (may have 1-3 substituted moieties α ₁ ), more preferably phenylsulfonyl group (may have 1-3 substituted moieties α ₁ ), most preferably benzene Sulfonyl (may have 1 substituent moiety α ₁ ).

When R ₁ , R ₂ and R ₃ represent "C ₇ -C ₁₆ aralkylsulfonyl group (may have 1 to 5 substituent moieties α ₁ on the aryl group)", examples of the group having a substituted moiety There are methylbenzylsulfonyl, acetylbenzylsulfonyl, benzoylbenzylsulfonyl, biphenylmethylsulfonyl, methylbiphenylmethylsulfonyl, methylnaphthylmethylsulfonyl, Acetylnaphthylmethylsulfonyl, Benzoylnaphthylmethylsulfonyl, Methylphenethylsulfonyl, Acetylphenethylsulfonyl, Methylnaphthylethylsulfonyl, Acetylnaphthylethyl Sulfonyl, methylphenylbutylsulfonyl, acetylphenylbutylsulfonyl, methylnaphthylbutylsulfonyl, and acetylnaphthylbutylsulfonyl. Preferably the group is a C ₇ -C ₁₆ aralkylsulfonyl group (which may have 1-3 substituent moieties α ₁ on the aryl group), more preferably a phenyl C ₁ -C ₆ alkylsulfonyl group (on the phenyl may have 1-3 substituent moieties α ₁ ), more preferably phenyl C ₁ -C ₄ alkylsulfonyl (may have 1 substituent moiety α ₁ on phenyl), most preferably benzylsulfonyl or phenethyl Sulfonyl (may have one substituent moiety α on the phenyl group).

When Z ₁ and Z ₄ represent "C ₆ -C ₁₀ aryloxy (may have 1-5 substituted moieties α ₁ )", examples of said groups having substituted moieties include methylphenoxy, trifluoro Methylphenoxy, hydroxyphenoxy, 4-hydroxy-2,3,5-trimethylphenoxy, 3,5-di-tert-butyl-4-hydroxyphenoxy, cyclopropylphenoxy , adamantylphenoxy, cyanophenoxy, nitrophenoxy, 4-amino-3,5-dimethylphenoxy, acetylphenoxy, methoxyphenoxy, benzoyl Phenoxy, fluorophenoxy, difluorophenoxy, chlorophenoxy, dichlorophenoxy, nitrophenoxy, (dimethylamino)phenoxy, 4-(4-trifluoromethyl phenylcarbamoylamino)-3,5-dimethylphenoxy, biphenoxy, methylbiphenoxy, dimethylaminophenoxy, methylnaphthyloxy, trifluoronaphthyloxy hydroxynaphthyloxy, methoxynaphthyloxy, fluoronaphthyloxy and chloronaphthyloxy. Preferably the group is C ₆ -C ₁₀ aryloxy (may have 1-3 substituted moieties α ₁ ), more preferably phenoxy (may have 1-5 substituted moieties α ₁ ), even more preferably phenoxy (may have 1 or 2 substituting moieties α ₁ ), most preferably phenoxy (may have 1 substituting moiety α ₁ ).

When Z ₁ and Z ₄ represent "C ₇ -C ₁₆ aralkyloxy group (may have 1-5 substituent moieties α ₁ on the aryl group)", examples of said groups having substituted moieties include methylbenzyl Oxygen, trifluoromethylbenzyloxy, hydroxybenzyloxy, 4-hydroxy-2,3,5-trimethylbenzyloxy, 3,5-di-tert-butyl-4-hydroxybenzyloxy, adamantine Benzyloxy, 4-amino-3,5-dimethylbenzyloxy, acetylbenzyloxy, methoxybenzyloxy, benzoylbenzyloxy, fluorobenzyloxy, difluorobenzyloxy , chlorobenzyloxy, dichlorobenzyloxy, nitrobenzyloxy, (dimethylamino)benzyloxy, biphenylmethoxy, methylbiphenylmethoxy, methylphenethoxy , Trifluoromethylphenylethoxy, hydroxyphenylethoxy, 4-hydroxy-2,3,5-trimethylphenethoxy, 3,5-di-tert-butyl-4-hydroxyphenylethoxy , adamantylphenylethoxy, 4-amino-3,5-dimethylphenethoxy, acetylphenethoxy, methoxyphenethoxy, benzoylphenethoxy, fluorophenylethyl Oxygen, difluorophenethoxy, chlorophenethoxy, nitrophenethoxy, (dimethylamino)phenethoxy, biphenylethoxy, methylbiphenylethoxy, Methylphenylbutoxy, trifluoromethylphenylbutoxy, hydroxyphenylbutoxy, 4-hydroxy-2,3,5-trimethylphenylbutoxy, 3,5-di-tert Butyl-4-hydroxyphenylbutoxy, adamantylphenylbutoxy, 4-amino-3,5-dimethylphenylbutoxy, acetylphenylbutoxy, methoxyphenyl Butoxy, fluorophenylbutoxy, chlorophenylbutoxy, nitrophenylbutoxy, (dimethylamino)phenylbutoxy, biphenylbutoxy, methylnaphthylmethyl oxy, trifluoronaphthylmethoxy, hydroxynaphthylmethoxy, methoxynaphthylmethoxy, fluoronaphthylmethoxy and chloronaphthylmethoxy. Preferably the group is a C ₇ -C ₁₆ aralkoxy group (which may have 1-3 substituent moieties α ₁ on the aryl group), more preferably a phenyl C ₁ -C ₆ alkoxy group (which may have 1-3 substituent moieties α ₁ ), more preferably phenyl C ₁ -C ₆ alkoxyl group (may have 1 substituent moiety α ₁ on phenyl), more preferably phenyl C ₁ -C ₄ alkoxyl group (may have 1 substituent α ₁ on phenyl), most preferably phenyl C ₁ -C ₂ alkoxy (may have 1 substituent α ₁ on phenyl).

When Z ₁ and Z ₄ represent "a saturated heterooxyl group (may have 1 to 5 substituent moieties α ₁ )", the group mainly represents a monovalent group derived from a monosaccharide. Examples of the monosaccharide include pentose sugars such as arabinose, xylose, and ribose, hexose sugars such as glucose, galactose, and mannose, amino sugars such as glucosamine and 2-galactosamine, and uronic acids such as glucuronic acid. . Preferably, the group is a monovalent group derived from a monosaccharide having physiological activity in a warm-blooded animal (especially human), more preferably a monovalent group obtained from uronic acid, particularly preferably from glucose A monovalent group derived from uronic acid.

When Z ₂ and Z ₃ represent "a saturated heterocyclic group (may have 1 to 5 substituent moieties α ₁ )", the group mainly represents a monovalent group obtained by removing a hydroxyl group from the above-mentioned monosaccharide. Preferably, the group is a monovalent group derived from a physiologically active monosaccharide in a warm-blooded animal (especially a human being), more preferably a monovalent group obtained from uronic acid, particularly preferably from glucose A monovalent group derived from an aldehyde acid.

When Z ₁ and Z ₄ represent "monocyclic type heteroaryl epoxy group (may have 1-5 substituent moieties α ₁ )", examples of the group having substituted moieties include fluorofuryloxy, fluoro Thiopheneoxy, fluoropyrroleoxy, fluorooxazolyloxy, fluorothiazolyloxy, fluorotriazolyloxy, fluoropyranyloxy, fluoropyridyloxy, fluoropyridazinyloxy, fluorine Pyrimidinyloxy, methylfuryloxy, methylthienyloxy, methylpyrroleoxy, methyloxazolyloxy, methylthiazolyloxy, methylpyridinyloxy, methoxyfuryloxy, methyl Oxythiopheneoxy, methoxypyrroleoxy, methoxyoxazolyloxy, methoxythiazolyloxy, methoxypyridinyloxy, dimethylaminofuryloxy, dimethylaminothienyloxy , dimethylaminopyrroleoxy, dimethylaminooxazolyloxy, dimethylaminothiazolyloxy and dimethylaminopyridyloxy, etc. Preferably, the group is a monocyclic heteroaryl epoxy group (may have 1-3 substituents α ₁ ), more preferably a 5- or 6-membered monocyclic heteroaryl epoxy group (may have 1 or 2 substituent moiety α ₁ ), more preferably a 5- or 6-membered monocyclic heteroaryl epoxy group (may have 1 substituent moiety α ₁ ), most preferably a 5- or 6-membered monocyclic type having 1 or 2 heteroatoms Heteroaryloxy group (may have one substituent moiety α ₁ ).

When Z ₁ and Z ₄ represent "C ₆ -C ₁₀ arylthio (may have 1-5 substituted moieties α ₁ )", examples of the group having substituted moieties include methylphenylthio, trifluoromethane phenylthio, hydroxyphenylthio, 4-hydroxy-2,3,5-trimethylphenylthio, 3,5-di-tert-butyl-4-hydroxyphenylthio, adamantylphenylthio, 4 -Amino-3,5-dimethylphenylthio, acetylphenylthio, methoxyphenylthio, benzoylphenylthio, fluorophenylthio, difluorophenylthio, chlorophenylthio Dichlorophenylthio, nitrophenylthio, (dimethylamino)phenylthio, biphenylthio, methylbiphenylthio, methylnaphthylthio, trifluoronaphthylthio, hydroxynaphthalene Thio, methoxynaphthylthio, fluoronaphthylthio and chloronaphthylthio. Preferably, the group is a C ₆ -C ₁₀ arylthio group (may have 1-3 substituents α ₁ ), more preferably a phenylthio group (may have 1-3 substituents α ₁ ), even more preferably a phenylthio group (may have 1 or 2 substituent moieties α ₁ ), most preferably phenylthio (may have 1 substituent moiety α ₁ ).

When Z ₁ and Z ₄ represent "C ₇ -C ₁₆ aralkylthio group (the aryl group may have 1-5 substituent moieties α ₁ )", examples of the group having substituted moieties include methylbenzylthio Base, trifluoromethylbenzylthio, hydroxybenzylthio, 4-hydroxy-2,3,5-trimethylbenzylthio, 3,5-di-tert-butyl-4-hydroxybenzylthio, adamantyl Benzylthio, 4-amino-3,5-dimethylbenzylthio, acetylbenzylthio, methoxybenzylthio, benzoylbenzylthio, fluorobenzylthio, difluorobenzylthio, Chlorobenzylthio, dichlorobenzylthio, nitrobenzylthio, (dimethylamino)benzylthio, biphenylmethylthio, methylbiphenylmethylthio, methylphenethylthio, Trifluoromethylphenethylthio, hydroxyphenethylthio, 4-hydroxy-2,3,5-trimethylphenethylthio, 3,5-di-tert-butyl-4-hydroxyphenethylthio, Adamantyl phenethylthio, 4-amino-3,5-dimethylphenethylthio, acetylphenethylthio, methoxyphenethylthio, benzoylphenethylthio, fluorophenethylthio Difluorophenylethylthio, chlorophenethylthio, nitrophenethylthio, (dimethylamino)phenethylthio, biphenylethylthio, methylbiphenylethylthio, methyl phenylbutylthio, trifluoromethylphenylbutylthio, hydroxyphenylbutylthio, 4-hydroxy-2,3,5-trimethylphenylbutylthio, 3,5-di-tert-butyl-4- Hydroxyphenylbutylthio, adamantylphenylbutylthio, 4-amino-3,5-dimethylphenylbutylthio, acetylphenylbutylthio, methoxyphenylbutylthio, fluorophenylbutylthio, Chlorophenylbutylthio, nitrophenylbutylthio, (dimethylamino)phenylbutylthio, biphenylbutylthio, methylnaphthylmethylthio, trifluoronaphthylmethylthio, hydroxynaphthylmethylthio , methoxynaphthylmethylthio, fluoronaphthylmethylthio and chloronaphthylmethylthio. Preferably the group is a C ₇ -C ₁₆ aralkylthio group (which may have 1-3 substituent moieties α ₁ on the aryl group), more preferably a phenyl C ₁ -C ₆ alkylthio group (which may have 1-3 substituent moieties α ₁ ), more preferably phenyl C ₁ -C ₆ alkylthio group (may have 1 substituent moiety α ₁ on phenyl), more preferably phenyl C ₁ -C ₄ alkylthio group (may have 1 substituent moiety α ₁ on phenyl), most preferably phenyl C ₁ -C ₂ alkylthio group (may have 1 substituent moiety on phenyl group).

When Z ₁ and Z ₄ represent "saturated heterocyclic thio group (may have 1-5 substituted moieties α ₁ )", examples of the group having substituted moieties include methylpyrrolidinylthio, methoxypyrrole Alkylthio, methyltetrahydrofurylthio, methoxytetrahydrofurylthio, methylpiperidinylthio, methoxypiperidinylthio, methyltetrahydropyranylthio, methoxy Tetrahydropyranylthio, Methyltetrahydrothiopyranylthio, Methoxytetrahydrothiopyranylthio, Methylpiperazinylthio, Methoxypiperazinylthio, Methylmorpholine Thio, methoxymorpholinothio, methylthiomorpholinothio and methoxythiomorpholinothio. Preferably, the group is a 5- or 6-membered saturated heterocyclic thio group (which may have 1-5 substituent moieties α ₁ ), more preferably a 5- or 6-membered saturated heterocyclic thio group (which may have 1-3 substituent moieties α ₁ ), most preferably a 5- or 6-membered saturated heterocyclic thio group (may have 1 substituent moiety α ₁ ).

When Z ₁ and Z ₄ represent "monocyclic type heteroaryl ring thio group (may have 1-5 substituted moieties α ₁ )", examples of the group having substituted moieties include fluorofurylthio, fluorothiophene Sylthio, fluoropyrrolylthio, fluorooxazolylthio, fluorothiazolylthio, fluorotriazolylthio, fluoropyranylthio, fluoropyridylthio, fluoropyridazinylthio, Fluoropyrimidinylthio, methylfurylthio, methylthienylthio, methylpyrrolylthio, methyloxazolylthio, methylthiazolylthio, methylpyridylthio, methyl Oxyfurylthio, methoxythienylthio, methoxypyrrolylthio, methoxyoxazolylthio, methoxythiazolylthio, methoxypyridylthio, dimethyl Aminofurylthio, Dimethylaminothienylthio, Dimethylaminopyrrolylthio, Dimethylaminooxazolylthio, Dimethylaminothiazolylthio and Dimethylaminopyridyl Sulfur base. Preferably, the group is a 5-7-membered monocyclic heteroaryl thio group (may have 1-3 substituting moieties α ₁ ), more preferably a 5- or 6-membered monocyclic heteroaryl thio group (may have 1 or 2 substituent moieties α ₁ ), more preferably a 5- or 6-membered monocyclic heteroaryl ring thio group (may have 1 substituent moiety α ₁ ), most preferably a 5- or 6-membered heteroaryl ring having 1 or 2 heteroatoms Monocyclic type heteroaryl ringthio group (may have one substituent moiety α ₁ ).

When Z ₁ and Z ₄ represent "amino group (may have 1 or 2 substituted moieties α ₁ )", examples of the group include amino, methylamino, ethylamino, propylamino, isopropylamino, Butylamino, sec-butylamino, tert-butylamino, pentylamino, hexylamino, dimethylamino, diethylamino, N-ethyl-N-methylamino, dipropylamino, dibutylamino Amino, dipentylamino, dihexylamino, phenylamino, 1- or 2-indenylamino, 1- or 2-naphthylamino, diphenylamino, formylamino, acetylamino, propionylamino, Butyrylamino, isobutyrylamino, valerylamino, isovalerylamino, pivaloylamino, hexanoylamino, acrylamino, methacrylamino, crotonylamino, benzoylamino, 1-indan Carbonylamino, 1- or 2-naphthoylamino, 2,6-diisopropylbenzoylamino, 1-indanecarbonylamino, 1- or 2-naphthoylamino, phenylacetylamino, 3 -Phenylpropionylamino, 4-phenylbutyrylamino, 5-phenylpentanoylamino, 6-phenylhexanoylamino, cyclopropanecarbonylamino, cyclobutanecarbonylamino, cyclopentanecarbonylamino, cyclohexane Alkylcarbonylamino, pyrrolylcarbonylamino, imidazolylcarbonylamino, pyrazolylcarbonylamino, triazolylcarbonylamino, tetrazolylcarbonylamino, nicotinoylamino, isonicotinoylamino, pyrazinylcarbonylamino, pyrimidinylcarbonyl Amino, pyridazinylcarbonylamino, thiazolylcarbonylamino, oxazolylcarbonylamino, oxadiazolylcarbonylamino, thiadiazolylcarbonylamino, 4-trifluoromethylphenylcarbamoylamino, N,N- Diacetylamino, N-formyl-N-hexylamino, N-acetyl-N-methylamino, N-acetyl-N-ethylamino, N-acetyl-N-propylamino, N- Acetyl-N-butylamino, N-acetyl-N-pentylamino, N-acetyl-N-hexylamino, N-benzoyl-N-methylamino, N-benzoyl-N- Ethylamino, N-benzoyl-N-propylamino, N-benzoyl-N-butylamino, N-benzoyl-N-pentylamino, N-benzoyl-N-hexylamino , N-benzoyl-N-phenylamino, N-benzyl-N-benzoylamino, N-hexyl-N-1-naphthoylamino, N-hexyl-N-2-naphthoylamino , N-hexyl-N-phenylacetylamino, N-isobutyl-N-cycloheptanecarbonylamino, N-butyl-N-nicotinylamino, N-hexyl-N-nicotinylamino and N- Isonicotinoyl-N-hexylamino. Preferably said group is amino (which may have 1 or 2 selected from C ₁ -C ₆ alkyl, C ₁ -C ₇ aliphatic acyl, C ₆ -C ₁₀ aryl which may have 1-3 substituted moieties β , a C ₇ -C ₁₆ aralkyl group that may have 1 to 3 substituent moieties β on the aryl group, a substituted moiety of a C ₇ -C ₁₁ arylcarbonyl group that may have 1 to 3 substituent moieties β on the aryl group), More preferably amino (can have 1 or 2 selected from C ₁ -C ₄ alkyl, C ₁ -C ₂ aliphatic acyl, phenyl that can have 1 substituting moiety β, can have 1 substituting moiety on phenyl β phenyl C ₁ -C ₄ alkyl, a substituted moiety of β benzoyl on the phenyl group).

Since the α-substituted carboxylic acid derivatives of the compounds (I)-(IV) of the present invention have a carboxyl group, they can be converted into salts by conventional methods. Examples of such salts are alkali metal salts such as sodium salt, potassium salt, lithium salt; alkaline earth metal salts such as calcium salt, magnesium salt; metal salts such as aluminum salt, iron salt, zinc salt, copper salt, nickel salt, cobalt salt, etc. ; Inorganic salts such as ammonium salts; organic salts and other amine salts such as tert-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylaminoacetic acid alkyl ester salts, ethylenediamine salts, N- Methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-N-phenethylamine salt, piperazine salt, tetramethylammonium salt, tris(hydroxymethyl)aminomethane salt.

The α-substituted carboxylic acid derivatives of the above-mentioned general formulas (I)-(IV) of the present invention can be converted into Salt. Examples of such salts are hydrohalic acids such as hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid salts; inorganic acid salts such as nitrates, perchlorates, sulfates, phosphates, etc.; lower alkanesulfonic acids Such as salts of methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid; salts of arylsulfonic acids such as benzenesulfonic acid, p-toluenesulfonic acid, etc.; salts of amino acids such as glutamic acid, aspartic acid, etc.; carboxylic acids Organic acids such as salts of fumaric acid, succinic acid, citric acid, tartaric acid, oxalic acid, and maleic acid; and amino acid salts such as ornithine, glutamate, and aspartate. Hydrohalide salts and organic acid salts are preferred.

The α-substituted carboxylic acid derivatives of the above general formulas (I)-(IV) of the present invention can be converted into pharmaceutically acceptable esters according to conventional methods. Compared with the α-substituted carboxylic acid derivatives with the above general formulas (I)-(IV), as long as the pharmaceutically acceptable esters of the α-substituted carboxylic acid derivatives with the above general formulas (I)-(IV) If it is medically usable and pharmaceutically acceptable, it is not particularly limited.

Examples of esters of α-substituted carboxylic acid derivatives of the above general formula (I)-(IV) of the present invention are C ₁ -C ₆ alkyl, C ₇ -C ₁₉ aralkyl or C ₁ -C ₇ fatty C ₁ -C ₆ alkyl substituted by acyloxy group, C ₁ -C ₆ alkyl substituted by C ₁ -C ₇ alkoxycarbonyloxy, C ₅ -C ₇ cycloalkylcarbonyloxy substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl substituted by C ₆ -C ₈ cycloalkoxycarbonyloxy, C ₁ -C ₆ alkyl substituted by C ₇ -C ₁₁ arylcarbonyloxy , C ₁ -C ₆ alkyl substituted by C ₇ -C ₁₁ aryloxycarbonyloxy, and 2-oxo-1,3-dioxa with a C ₁ -C ₆ alkyl substituent at the 5-position Pentacycl-4-ylmethyl.

For ester residues,

Examples of C ₁ -C ₆ alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, methylbutyl, dimethylpropyl radical, ethylpropyl, hexyl, methylpentyl, dimethylbutyl, ethylbutyl and trimethylpropyl. Preferably C ₁ -C ₄ alkyl, more preferably methyl, ethyl, propyl, isopropyl, butyl or isobutyl, most preferably methyl or ethyl.

Examples of C ₇ -C ₁₉ aralkyl groups are benzyl, phenethyl, phenylpropyl, phenylbutyl, naphthylmethyl and bibenzyl. Benzyl is preferred.

Examples of C ₅ -C ₇ cycloalkyl are cyclopentyl, cyclohexyl and cycloheptyl. Cyclohexyl is preferred.

Examples of C ₆ -C ₁₀ aryl are phenyl and naphthyl, preferably phenyl.

Specific examples of preferred ester residues are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, benzyl, acetoxymethyl, 1-(acetoxy)ethyl, Base, propionyloxymethyl, 1-propionyloxyethyl, butyryloxymethyl, 1-butyryloxyethyl, 1-isobutyryloxyethyl, valeryloxymethyl , 1-pentanoyloxyethyl, isovaleryloxymethyl, 1-isovaleryloxyethyl, pivaloyloxymethyl, 1-pivaloyloxyethyl, methoxycarbonyl Oxymethyl, 1-methoxycarbonyloxyethyl, ethoxycarbonyloxymethyl, 1-ethoxycarbonyloxyethyl, propoxycarbonyloxymethyl, 1-propoxy Carbonyloxyethyl, isopropoxycarbonyloxymethyl, 1-isopropoxycarbonyloxyethyl, butoxycarbonyloxymethyl, 1-butoxycarbonyloxyethyl, isobutyl Oxycarbonyloxymethyl, 1-isobutoxycarbonyloxyethyl, tert-butoxycarbonyloxymethyl, 1-(tert-butoxycarbonyloxy)ethyl, cyclopentanecarbonyloxy Methyl, 1-cyclopentanecarbonyloxyethyl, cyclohexanecarbonyloxymethyl, 1-cyclohexanecarbonyloxyethyl, cyclopentyloxycarbonyloxymethyl, 1-cyclopentyloxy Carbonyloxyethyl, cyclohexyloxycarbonyloxymethyl, 1-cyclohexyloxycarbonyloxyethyl, benzoyloxymethyl, 1-benzoyloxyethyl, phenoxycarbonyl Oxymethyl, 1-phenoxycarbonyloxyethyl and 5-methyl-2-oxo-1,3-dioxolan-4-ylmethyl.

The amide of the α-substituted carboxylic acid derivative of the above-mentioned general formula (I)-(IV) of the present invention means the substance obtained by the dehydration condensation of the carboxyl group of the α-substituted carboxylic acid derivative and ammonia, specifically, the carboxyl group is converted It is a derivative of -CONH ₂ group.

The compounds of the present invention also include various isomers.

For example, the α-substituted carboxylic acid derivatives of the above-mentioned general formulas (I)-(IV) have optical isomers because the carbon at the 2-position is an asymmetric carbon, and the substituent also has an asymmetric carbon.

That is, the α-position carbon bonded to R ₂ , Y, and the nitrogen atom is an asymmetric carbon atom, and there are stereoisomers of R coordination and S coordination. Various isomers or compounds of any ratio thereof are also included in the present invention. The α-substituted carboxylic acid derivatives of compounds (I)-(IV) can be synthesized using the raw material compounds after optical resolution, or the synthesized compounds (I)-(IV) can be synthesized by the usual optical resolution method or separation method as needed. α-Substituted carboxylic acid derivatives can be partitioned, or asymmetric synthesis can be used to obtain this stereoisomer.

Furthermore, when Y represents a sulfoxide group, the sulfur atom becomes an asymmetric center, and optical isomers exist. In this case, also, various isomers thereof or compounds in any ratio thereof are also included in the present invention, and can be obtained by dividing by ordinary optical division or separation, or by asymmetric synthesis. This stereoisomer.

In addition, compounds having double bonds in the carbon chain also have geometric isomerism.

The present invention includes all such isomers.

Moreover, compounds (I)-(IV) of the present invention may absorb moisture due to standing in the air and recrystallize, become hydrates by attaching and absorbing water, and form solvates, all of which are included in the present invention .

In addition, the compounds (I)-(IV) of the present invention can also absorb other kinds of solvents to form solvates, and such substances are also included in the scope of the present invention.

In addition, the present invention also includes compounds that are metabolized in vivo into the α-substituted carboxylic acid derivatives of the compounds (I)-(IV) of the present invention or pharmaceutically acceptable salts thereof, so-called prodrugs.

Furthermore, the α-substituted carboxylic acid derivatives of the compounds (I)-(IV) of the present invention, their pharmaceutically acceptable esters or their pharmaceutically acceptable amides or their pharmaceutically acceptable salts are combined to form a drug Examples of agents of the composition include sulfonylureas, α-glucosidase inhibitors, aldose reductase inhibitors, biguanides, statins, squalene synthesis inhibitors, fibrates, LDL metabolization accelerators, vascular Tensin II antagonists, angiotensin converting enzyme inhibitors, antineoplastic agents and RXR activators.

The aforementioned sulfonylureas are drugs that promote insulin secretion, and examples thereof include tolbutamide, hexylurea acetate, tolazamide, and chlorpropamide.

The above-mentioned α-glucosidase inhibitors are drugs that inhibit digestive enzymes such as amylase, maltase, α-dextrinase, and sucrase, and delay digestion of starch and sucrose. Examples include acarbose, N-(1 , 3-dihydroxy-2-propyl) effective olamine (common name: voglibose), miglitol, etc.

The above-mentioned aldose reductase inhibitors are drugs that inhibit diabetic complications by inhibiting the rate-limiting enzyme of the initial step of the polyol route, examples of which include torristat, epalrestat, 2,7-difluoro- Spiro(9H-fluorene-9,4'-imidazolidine)-2',5'-dione (common name: mirestat), 3-[(4-bromo-2-fluorophenyl)methyl] -7-Chloro-3,4-dihydro-2,4-dioxo-1(2H)-quinazolineacetic acid (common name: Zenastat), 6-fluoro-2,3-dihydro-2 ',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxylamine (SNK-860), zopolrestat, sobinil, 1- [(3-Bromo-2-benzofuryl)sulfonyl]-2,4-imidazolidinedione (M-16209) and the like.

The above-mentioned biguanides are drugs having anaerobic glycolysis promoting action, peripheral blood insulin enhancing action, glucose intestinal absorption inhibiting action, glycogen regeneration inhibiting action, fatty acid oxidation inhibiting action, etc. Examples thereof include phenformin and metformin. , Ding Fuming, etc.

The aforementioned statin compounds are drugs that lower blood cholesterol by inhibiting hydroxymethylglutaryl CoA (HMG-CoA) reductase, examples of which include pravastatin and its sodium salt, simvastatin, lovastatin, atorvastatin, celivastatin, fluvastatin, etc.

The aforementioned squalene synthesis inhibitors are drugs that lower blood cholesterol by inhibiting the synthesis of squalene, examples of which include (S)-α-[bis(2,2-dimethyl-1-oxopropoxy ) Methoxy]phosphinyl-3-phenoxybenzenebutanesulfonic acid monopotassium salt (BMS-188494), etc.

The above-mentioned fibrates are drugs that lower blood triglycerides by inhibiting the synthesis and secretion of triglycerides in the liver and activating lipoprotein lipase. Examples include bezafibrate, benzclofibrate, Niberate, siprofibrate (cyprofibrate), Clifibrate, Clofibrate, Clofibrate, Etofibrate, Fenofibrate, Gemfibrozil, Nicofibrate, Pifibrate, Clofibrate Special, Double Bet and Theofibrate (theofibrate) and so on.

The above-mentioned LDL dissimilation accelerator is a drug that lowers blood cholesterol by increasing LDL (low-density lipoprotein) receptors, such as compounds or salts thereof described in JP-A 7-316144, and specific examples include N-[2-[4- Bis(4-fluorophenyl)methyl-1-piperazinyl]ethyl]-7,7-diphenyl-2,4,6-heptatrienoic acid amide, etc.

The above-mentioned statin compounds, squalene synthesis inhibitors, fibrates and LDL dissimilation accelerators can be replaced by other agents that have the effect of lowering blood cholesterol and triglycerides. Niacin derivative preparations such as tetranicotinyl ester, antioxidants such as probucol, ion exchange resin preparations such as cholestyramine, etc.

The above-mentioned angiotensin II antagonist is a drug that strongly suppresses the increase in blood pressure and lowers blood pressure through angiotensin II. Examples of such drugs include losartan potassium, candesartan cilexetil, valsartan, and termisartan. , オルメサルタン (ormesartan), etc.

The above-mentioned angiotensin-converting enzyme inhibitors are drugs that lower blood pressure by inhibiting angiotensin-converting enzyme while partially lowering blood sugar in diabetic patients, and examples thereof include captopril, enalapril, alazapril, delapril , ramipril, lisinopril, imidapril, benazepril, cilopril, cilazapril, enalaprilat, fosinopril, movipril, perindopril , Quinapril, Spiropril, Temopril, Trandolapril, etc.

The α-substituted carboxylic acid derivatives having the above general formula (I) are preferably:

(1) R ₁ , R ₂ and R ₃ are the same or different, representing (i) hydrogen atom, (ii) C ₁ -C ₆ alkyl group, (iii) C ₆ -C ₁₀ aryl group (can have 1-3 Substituent moiety α ₁ ), (iv) C ₇ -C ₁₆ aralkyl (1-3 substituent moieties α ₁ may be present on aryl), (v) C ₁ -C ₄ alkylsulfonyl or (vi) α-substituted carboxylic acid derivatives of C ₁ -C ₆ haloalkylsulfonyl groups, their pharmaceutically acceptable esters, or their pharmaceutically acceptable amides or their pharmaceutically acceptable salts.

(2) R ₁ , R ₂ and R ₃ are the same or different, representing (i) a hydrogen atom, (ii) a C ₁ -C ₄ alkyl group, (iii) a phenyl group (may have one substituent α ₁ ), ( iv) α-substituted carboxylic acid derivatives of phenyl C ₁ -C ₂ alkyl (which may have 1-3 substituent moieties α ₁ on the phenyl group) or (v) C ₁ -C ₂ alkylsulfonyl, their A pharmaceutically acceptable ester, or a pharmaceutically acceptable amide thereof, or a pharmaceutically acceptable salt thereof.

(3) R ₁ , R ₂ and R ₃ are the same or different, representing (i) hydrogen atom, (ii) C ₁ -C ₄ alkyl group or (iii) benzyl group (the phenyl group may have 1 substituent α ₁ ) α-substituted carboxylic acid derivatives, their pharmaceutically acceptable esters, or their pharmaceutically acceptable amides or their pharmaceutically acceptable salts.

(4) R ₁ represents a C ₁ -C ₂ alkyl group, R ₂ represents a hydrogen atom, R ₃ represents a C ₁ -C ₄ alkyl group or a phenyl C ₁ -C ₄ alkyl group (the phenyl group may have 1 substitution α-substituted carboxylic acid derivatives of moiety α ₁ ), their pharmaceutically acceptable esters, or their pharmaceutically acceptable amides or their pharmaceutically acceptable salts.

(5) R ₁ represents a C ₁ -C ₂ alkyl group, R ₂ represents a hydrogen atom, and R ₃ represents an α-substituted carboxylic acid derivative of a hydrogen atom, its pharmaceutically acceptable esters, or its pharmaceutically acceptable Amides or pharmaceutically acceptable salts thereof.

(6) R ₁ represents a C ₁ -C ₂ alkyl group, R ₂ represents a hydrogen atom, and R ₃ represents an α-substituted carboxylic acid derivative of a phenyl group (may have one substituent part α ₁ ), and its pharmaceutically acceptable Esters, or pharmaceutically acceptable amides or pharmaceutically acceptable salts thereof.

(7) R ₁ represents a C ₁ -C ₂ alkyl group, R ₂ represents a hydrogen atom, and R ₃ represents an α-substituted carboxylic acid derivative of a phenyl group (may have one substituent part α ₁ ), and its pharmaceutically acceptable Esters, or pharmaceutically acceptable amides or pharmaceutically acceptable salts thereof.

(8) R ₁ represents a C ₁ -C ₂ alkyl group, R ₂ represents a hydrogen atom, R ₃ represents an α-substituted carboxylic acid derivative of a C ₁ -C ₂ alkyl sulfonyl group, its pharmaceutically acceptable esters, or a pharmaceutically acceptable amide thereof or a pharmaceutically acceptable salt thereof.

(9) A represents an α-substituted carboxylic acid derivative of a nitrogen atom, a pharmaceutically acceptable ester thereof, or a pharmaceutically acceptable amide or a pharmaceutically acceptable salt thereof.

(10) A represents α-substituted carboxylic acid derivatives with =CH-group, their pharmaceutically acceptable esters, or their pharmaceutically acceptable amides or their pharmaceutically acceptable salts.

(11) B represents an α-substituted carboxylic acid derivative of an oxygen atom, a pharmaceutically acceptable ester thereof, or a pharmaceutically acceptable amide thereof or a pharmaceutically acceptable salt thereof.

(12) B represents an α-substituted carboxylic acid derivative of a sulfur atom, a pharmaceutically acceptable ester thereof, or a pharmaceutically acceptable amide or a pharmaceutically acceptable salt thereof.

(13) W ₁ represents α-substituted carboxylic acid derivatives of C ₁ -C ₆ alkylene groups, their pharmaceutically acceptable esters, or their pharmaceutically acceptable amides or their pharmaceutically acceptable salts.

(14) W ₁ represents α-substituted carboxylic acid derivatives of C ₁ -C ₄ alkylene groups, their pharmaceutically acceptable esters, or their pharmaceutically acceptable amides or their pharmaceutically acceptable salts.

(15) W ₁ represents α-substituted carboxylic acid derivatives of C ₁ -C ₂ alkylene groups, their pharmaceutically acceptable esters, or their pharmaceutically acceptable amides or their pharmaceutically acceptable salts.

(16) W ₁ represents a methylene α-substituted carboxylic acid derivative, a pharmaceutically acceptable ester thereof, or a pharmaceutically acceptable amide or a pharmaceutically acceptable salt thereof.

(17) W ₂ represents a single bond or a C ₁ -C ₆ alkylene α-substituted carboxylic acid derivative, its pharmaceutically acceptable ester, or its pharmaceutically acceptable amide, or its pharmaceutically acceptable Salt.

(18) W ₂ represents α-substituted carboxylic acid derivatives of C ₁ -C ₄ alkylene groups, their pharmaceutically acceptable esters, or their pharmaceutically acceptable amides or their pharmaceutically acceptable salts.

(19) W ₂ represents α-substituted carboxylic acid derivatives of C ₁ -C ₂ alkylene groups, their pharmaceutically acceptable esters, or their pharmaceutically acceptable amides or their pharmaceutically acceptable salts.

(20) W ₂ represents a methylene α-substituted carboxylic acid derivative, a pharmaceutically acceptable ester thereof, or a pharmaceutically acceptable amide or a pharmaceutically acceptable salt thereof.

(21) X represents (i) hydrogen atom, (ii) C ₁ -C ₄ alkyl, (iii) C ₁ -C ₂ haloalkyl, (iv) C ₁ -C ₄ alkoxy, (v) halogen atom , (vi) hydroxyl, (vii) cyano, (viii) nitro, (ix) C ₁ -C ₅ aliphatic acyl or (x) amino (may have 1 substituted moiety β) α-substituted carboxylic acid derivatization substances, their pharmaceutically acceptable esters, or their pharmaceutically acceptable amides or their pharmaceutically acceptable salts.

(22) X represents (i) a hydrogen atom, (ii) a C ₁ -C ₂ alkyl group, (iii) a halogen atom, (iv) a hydroxyl group, (v) a C ₁ -C ₂ aliphatic acyl group or (vi) an amino group α-substituted carboxylic acid derivatives, their pharmaceutically acceptable esters, or their pharmaceutically acceptable amides or their pharmaceutically acceptable salts.

(23) X represents an α-substituted carboxylic acid derivative of a hydrogen atom, a pharmaceutically acceptable ester thereof, or a pharmaceutically acceptable amide or a pharmaceutically acceptable salt thereof.

(24) Z ₁ represents (i) C ₁ -C ₄ alkoxy, (ii) C ₁ -C ₄ alkylthio, (iii) halogen atom, (iv) C ₆ -C ₁₀ aryloxy (may have 1-5 substituted moieties α ₁ ), (v) C ₇ -C ₁₆ aralkyloxy (1-3 substituted moieties α ₁ may be present on aryl), (vi) C ₆ -C ₁₀ cycloalkoxy (vii) saturated heterocyclic oxy group (may have 1-5 substituted moieties α ₁ ), (viii) C ₆ -C ₁₀ arylthio group (may have 1-5 substituted moieties α ₁ ), (ix) α-substituted carboxylic acid derivatives of saturated heterocyclic thio group (may have 1-5 substituent moiety α ₁ ), (x) amino group (may have 1 substituent moiety α ₁ ) or (xi) hydroxyl group, which can be pharmaceutically Acceptable esters, or pharmaceutically acceptable amides thereof, or pharmaceutically acceptable salts thereof.

(25) Z ₁ represents (i) C ₁ -C ₂ alkoxy, (ii) C ₁ -C ₂ alkylthio, (iii) halogen atom, (iv) phenoxy (can have 1-5 substitutions Moiety α ₁ ), (v) saturated heterocyclic oxy group (may have 1-5 substituted moieties α ₁ ), (vi) phenylthio group (may have 1-5 substituted moieties α ₁ ), (vii) saturated heterocyclic Epithiol (may have 1-5 substituted moieties α ₁ ), (viii) amino or (ix) hydroxy α-substituted carboxylic acid derivatives, their pharmaceutically acceptable esters, or their pharmaceutically acceptable Amides or pharmaceutically acceptable salts thereof.

(26) Z ₁ represents (i) C ₁ -C ₂ alkoxy, (ii) C ₁ -C ₂ alkylthio, (iii) phenoxy (may have 1-5 substituted moieties α ₁ ), ( iv) α-Substituted Carboxylic Acid Derivatization of Saturated Heterocyclic Oxygen (Can Have 1-5 Substituent Moieties α ₁ ), (v) Phenylthio (Can Have 1-5 Substituent Moieties α ₁ ) or (vi) Hydroxyl substances, their pharmaceutically acceptable esters, or their pharmaceutically acceptable amides or their pharmaceutically acceptable salts.

(27) Z ₁ represents (i) C ₁ -C ₂ alkoxy, (ii) phenoxy (may have 1-3 substituted moieties α ₁ ) or (iii) phenylthio (may have 1-3 [alpha]-substituted carboxylic acid derivatives, pharmaceutically acceptable esters thereof, or pharmaceutically acceptable amides or pharmaceutically acceptable salts thereof of the substituted moiety [alpha] ₁ ).

(28) The substituent moiety α ₁ represents (i) C ₁ -C ₆ alkyl, (ii) C ₁ -C ₂ haloalkyl, (iii) C ₁ -C ₄ alkoxy, (iv) halogen atom, (v ) hydroxyl, (vi) cyano, (vii) nitro, (viii) C ₆ -C ₁₀ cycloalkyl, (ix) C ₁ -C ₂ aliphatic acyl, (x) C ₇ -C ₁₁ arylcarbonyl (may have 1-3 substituted moieties β), (xi) carbamoyl, (xii) amino (may have 1 or 2 substituted moieties β) or (xiii) carboxyl α-substituted carboxylic acid derivatives, and their pharmaceutical Pharmaceutically acceptable esters, or pharmaceutically acceptable amides or pharmaceutically acceptable salts thereof.

(29) The substituent moiety α ₁ represents (i) C ₁ -C ₄ alkyl, (ii) C ₁ -C ₂ haloalkyl, (iii) C ₁ -C ₂ alkoxy, (iv) halogen atom, (v ) hydroxyl group, (vi) cyano group, (vii) nitro group, (viii) adamantyl group, (ix) benzoyl group (may have 1 substituent moiety β), (x) amino group (may have 1 substituent moiety β) Or (xi) α-substituted carboxylic acid derivatives of the carboxyl group, their pharmaceutically acceptable esters, or their pharmaceutically acceptable amides or their pharmaceutically acceptable salts.

(30) Substituent moiety α ₁ represents (i) C ₁ -C ₄ alkyl, (ii) halogen atom, (iii) hydroxyl, (iv) adamantyl, (v) benzoyl, (vi) amino (may have An α-substituted carboxylic acid derivative, a pharmaceutically acceptable ester thereof, or a pharmaceutically acceptable amide or a pharmaceutically acceptable salt thereof, which has one substituted moiety β) or (vii) carboxyl group.

(31) The substituent moiety α ₁ represents an α-substituted carboxylic acid derivative of (i) C ₁ -C ₄ alkyl, (ii) halogen atom, (iii) hydroxyl or (iv) adamantyl, its pharmaceutically acceptable Esters, or pharmaceutically acceptable amides or pharmaceutically acceptable salts thereof.

(32) The substituent moiety α ₁ represents an α-substituted carboxylic acid derivative of C ₁ -C ₄ alkyl or hydroxyl, its pharmaceutically acceptable ester, or its pharmaceutically acceptable amide, or its pharmaceutically acceptable Salt.

(33) The substituent moiety _α1 represents an α-substituted carboxylic acid derivative of a halogen atom or an adamantyl group, a pharmaceutically acceptable ester thereof, or a pharmaceutically acceptable amide thereof or a pharmaceutically acceptable salt thereof.

(34) The substituted moiety _α1 represents an α-substituted carboxylic acid derivative of a hydroxyl or carboxyl group, a pharmaceutically acceptable ester thereof, or a pharmaceutically acceptable amide or a pharmaceutically acceptable salt thereof.

(35) α-substituted carboxylic acid derivatives whose substituent moiety _α1 represents C ₁ -C ₄ alkyl, benzoyl or amino group (may have 1 substituent moiety β), pharmaceutically acceptable esters thereof, or A pharmaceutically acceptable amide or a pharmaceutically acceptable salt thereof.

(36) The substituent moiety _α1 represents an α-substituted carboxylic acid derivative of benzoyl, a pharmaceutically acceptable ester thereof, or a pharmaceutically acceptable amide thereof or a pharmaceutically acceptable salt thereof.

(37) The substituent β represents (i) C ₁ -C ₆ alkyl, (ii) halogen atom, (iii) phenyl (may have 1-3 substituent γ), (iv) phenyl C ₁ -C ₄ alkyl (can have 1-3 substituent moieties γ on phenyl), (v) C ₁ -C ₅ aliphatic acyl or (vi) phenylaminocarbonyl (can have 1-3 substituent moieties on phenyl α-substituted carboxylic acid derivatives of γ), their pharmaceutically acceptable esters, or their pharmaceutically acceptable amides or their pharmaceutically acceptable salts.

(38) The substituent β represents the α-substitution of (i) C ₁ -C ₄ alkyl, (ii) halogen atom or (iii) phenylaminocarbonyl (1-3 substituents γ on the phenyl group) Carboxylic acid derivatives, their pharmaceutically acceptable esters, or their pharmaceutically acceptable amides or their pharmaceutically acceptable salts.

(39) The substituent β represents an α-substituted carboxylic acid derivative of phenylaminocarbonyl (which may have one substituent γ on the phenyl group), its pharmaceutically acceptable ester, or its pharmaceutically acceptable amide or a pharmaceutically acceptable salt thereof.

(40) The substituted moiety γ represents (i) C ₁ -C ₂ alkyl, (ii) C ₁ -C ₂ haloalkyl, (iii) halogen atom or (iv) hydroxy α-substituted carboxylic acid derivative, and its pharmaceutical Pharmaceutically acceptable esters, or pharmaceutically acceptable amides or pharmaceutically acceptable salts thereof.

(41) The substituent moiety γ represents an α-substituted carboxylic acid derivative of a trifluoromethyl group or a halogen atom, a pharmaceutically acceptable ester thereof, or a pharmaceutically acceptable amide thereof or a pharmaceutically acceptable salt thereof.

(42) The substituted moiety γ represents an α-substituted carboxylic acid derivative of trifluoromethyl, a pharmaceutically acceptable ester thereof, or a pharmaceutically acceptable amide thereof or a pharmaceutically acceptable salt thereof.

Moreover, among the α-substituted carboxylic acid derivatives having the above general formula (I), it is preferred that R ₁ , R ₂ and R ₃ selected from (1)-(8) be selected from (9) or (10) A, B selected from (11) or (12), W ₁ selected from (13)-(16), W ₂ selected from (17)-(20), selected from (21)-(23) X, Z ₁ selected from (24)-(27), α ₁ selected from (28)-(36), β selected from (37)-(39), selected from (40)-(42) Compounds composed of γ.

For example, among the α-substituted carboxylic acid derivatives having the above general formula (I), the following compounds are preferred.

(43) α-substituted carboxylic acid derivatives, pharmaceutically acceptable esters thereof, or pharmaceutically acceptable amides or pharmaceutically acceptable salts thereof, wherein

R ₁ , R ₂ and R ₃ are the same or different, and represent (i) hydrogen atom, (ii) C ₁ -C ₆ alkyl group, (iii) C ₆ -C ₁₀ aryl group (may have 1-3 substituted moieties α ₁ ), (iv) C ₇ -C ₁₆ aralkyl (1-3 substituted moieties α ₁ may be present on the aryl), (v) C ₁ -C ₄ alkylsulfonyl or (vi) C ₁ - C ₆ haloalkylsulfonyl,

A represents =CH-group,

B represents an oxygen atom,

W ₁ represents a C ₁ -C ₄ alkylene group,

W ₂ represents a C ₁ -C ₄ alkylene group,

X represents (i) hydrogen atom, (ii) C ₁ -C ₄ alkyl, (iii) C ₁ -C ₂ haloalkyl, (iv) C ₁ -C ₄ alkoxy, (v) halogen atom, (vi ) hydroxy, (vii) cyano, (viii) nitro, (ix) C ₁ -C ₅ aliphatic acyl or (x) amino (may have 1 substituent moiety β),

Y represents an oxygen atom or an S(O)p group (p represents an integer of 0-2 in the formula),

Z ₁ represents (i) C ₁ -C ₄ alkoxy, (ii) C ₁ -C ₄ alkylthio, (iii) halogen atom, (iv) C ₆ -C ₁₀ aryloxy (can have 1-5 substituent moieties α ₁ ), (v) C ₇ -C ₁₆ aralkyloxy groups (1-3 substituent moieties α ₁ may be present on the aryl group), (vi) C ₆ -C ₁₀ cycloalkoxy groups, ( vii) saturated heterocyclic oxy group (may have 1-5 substituted moieties α ₁ ), (viii) C ₆ -C ₁₀ arylthio group (may have 1-5 substituted moieties α ₁ ), (ix) saturated heterocycle Thio group (may have 1-5 substituent moieties α ₁ ), (x) amino group (may have 1 substituent moiety α ₁ described below) or (xi) hydroxyl group,

The substituent moiety _α1 represents (i) C ₁ -C ₆ alkyl, (ii) C ₁ -C ₂ haloalkyl, (iii) C ₁ -C ₄ alkoxy, (iv) halogen atom, (v) hydroxyl, (vi) cyano, (vii) nitro, (viii) C ₆ -C ₁₀ cycloalkyl, (ix) C ₁ -C ₂ aliphatic acyl, (x) C ₇ -C ₁₁ arylcarbonyl (may have 1 - 3 substituted moieties β), (xi) carbamoyl, (xii) amino (can have 1 or 2 substituted moieties β) or (xiii) carboxyl,

The substituent β represents (i) C ₁ -C ₆ alkyl, (ii) halogen atom, (iii) phenyl (may have 1-3 substituent γ), (iv) phenyl C ₁ -C ₄ alkyl (may have 1-3 substituents γ on phenyl), (v) C ₁ -C ₅ aliphatic acyl or (vi) phenylaminocarbonyl (may have 1-3 substituents γ on phenyl) ,

The substituent moiety γ represents (i) a C ₁ -C ₂ alkyl group, (ii) a C ₁ -C ₂ haloalkyl group, (iii) a halogen atom or (iv) a hydroxyl group.

(44) α-substituted carboxylic acid derivatives, pharmaceutically acceptable esters thereof, or pharmaceutically acceptable amides or pharmaceutically acceptable salts thereof, wherein

R ₁ , R ₂ and R ₃ are the same or different, and represent (i) hydrogen atom, (ii) C ₁ -C ₄ alkyl group, (iii) phenyl group (may have 1 substituted moiety α ₁ ), (iv) benzene C ₁ -C ₂ alkyl (can have 1-3 substituents α ₁ on phenyl) or (v) C ₁ -C ₂ alkylsulfonyl,

A represents =CH-group,

B represents an oxygen atom,

W ₁ represents a C ₁ -C ₂ alkylene group,

W ₂ represents a C ₁ -C ₂ alkylene group,

X represents (i) hydrogen atom, (ii) C ₁ -C ₂ alkyl group, (iii) halogen atom, (iv) hydroxyl group, (v) C ₁ -C ₂ aliphatic acyl group or (vi) amino group,

Y represents an oxygen atom or an S(O)p group (wherein p represents an integer of 0-2),

Z ₁ represents (i) C ₁ -C ₂ alkoxy, (ii) C ₁ -C ₂ alkylthio, (iii) halogen atom, (iv) phenoxy (may have 1-5 substituted moieties α ₁ ), (v) saturated heterocyclic oxy group (may have 1-5 substituted moieties α ₁ ), (vi) phenylthio group (may have 1-5 substituted moieties α ₁ ), (vii) saturated heterocyclic thio group (may have 1-5 substituted moieties α ₁ ), (viii) amino or (ix) hydroxyl,

The substituent moiety _α1 represents (i) C ₁ -C ₄ alkyl, (ii) C ₁ -C ₂ haloalkyl, (iii) C ₁ -C ₂ alkoxy, (iv) halogen atom, (v) hydroxyl, (vi) cyano, (vii) nitro, (viii) adamantyl, (ix) benzoyl (may have 1 substituent β), (x) amino (may have 1 substituent β), or (xi )carboxyl,

The substituent β represents (i) C ₁ -C ₄ alkyl, (ii) a halogen atom or (iii) phenylaminocarbonyl (1-3 substituents γ may be present on the phenyl group),

The substituent γ represents a trifluoromethyl group or a halogen atom.

(45) α-substituted carboxylic acid derivatives, their pharmaceutically acceptable esters, or their pharmaceutically acceptable amides or their pharmaceutically acceptable salts, wherein

R ₁ , R ₂ and R ₃ are the same or different, and represent (i) hydrogen atom, (ii) C ₁ -C ₄ alkyl group or (iii) benzyl group (may have 1 substituent moiety α ₁ on the phenyl group) ,

A represents =CH-group,

B represents an oxygen atom,

W ₁ represents a C ₁ -C ₂ alkylene group,

W ₂ represents a methylene group,

X represents a hydrogen atom,

Y represents an oxygen atom or an S(O)p group (p represents an integer of 0-2 in the formula),

Z ₁ represents (i) C ₁ -C ₂ alkoxy, (ii) C ₁ -C ₂ alkylthio, (iii) phenoxy (may have 1-5 substituted moieties α ₁ ), (iv) saturated Heterocyclyloxy group (may have 1-5 substituted moieties α ₁ ), (v) phenylthio group (may have 1-5 substituted moieties α ₁ ) or (vi) hydroxyl,

The substituent moiety _α1 represents (i) C ₁ -C ₄ alkyl, (ii) halogen atom, (iii) hydroxyl, (iv) adamantyl, (v) benzoyl, (vi) amino (may have 1 substitution moiety β) or (vii) carboxyl,

The substituent β represents a phenylaminocarbonyl group (one substituent γ may be present on the phenyl group),

The substituent moiety γ represents a trifluoromethyl group.

In addition, among the α-substituted carboxylic acid derivatives having the above general formula (II), preferably

(46) Z ₂ represents an α-substituted carboxylic acid derivative of a 5- or 6-membered saturated heterocyclic group (which may have 1-5 substituted moieties α ₁ ) or phenyl (having 1-3 substituted moieties α ₂ ), Its pharmaceutically acceptable esters, or its pharmaceutically acceptable amides or its pharmaceutically acceptable salts.

(47) Z ₂ represents an α-substituted carboxylic acid derivative of tetrahydropyranyl (which may have 1-5 substituted moieties α ₁ ), a pharmaceutically acceptable ester thereof, or a pharmaceutically acceptable amide thereof, or its pharmaceutically acceptable salt.

(48) Z ₂ represents an α-substituted carboxylic acid derivative of phenyl (with 1 substituted moiety α ₂ ), its pharmaceutically acceptable ester, or its pharmaceutically acceptable amide, or its pharmaceutically acceptable Salt.

(49) Substituent moiety α ₂ represents (i) C ₆ -C ₁₀ cycloalkyl, (ii) phenyl (may have 1-3 substituent moieties β), (iii) phenylcarbonyl (may have 1-3 α-substituted carboxylic acid derivatives of substituted moiety β) or (iv) monocyclic heteroaryl ring carbonyl (may have 1-3 substituted moieties β), their pharmaceutically acceptable esters, or their pharmaceutically acceptable Accepted amides or pharmaceutically acceptable salts thereof.

(50) The substituent moiety _α2 represents an α-substituted carboxylic acid derivative of C ₆ -C ₁₀ cycloalkyl, its pharmaceutically acceptable ester, or its pharmaceutically acceptable amide or its pharmaceutically acceptable salt .

(51) The substituted moiety _α2 represents an α-substituted carboxylic acid derivative of adamantyl, a pharmaceutically acceptable ester thereof, or a pharmaceutically acceptable amide or a pharmaceutically acceptable salt thereof.

Moreover, among the α-substituted carboxylic acid derivatives having the above-mentioned general formula (II), it is preferred that R ₁ , R ₂ and R ₃ selected from (1)-(8) be selected from (9) or (10) A, B selected from (11) or (12), W ₁ selected from (13)-(16), W ₂ selected from (17)-(20), selected from (21)-(23) X, Z ₂ selected from (46)-(48), α 1 selected _from (28)-(36), α ₂ selected from (49)-(51), selected from (37)-(39 ) and γ selected from (40)-(42) are combined.

For example, among the α-substituted carboxylic acid derivatives having the above general formula (II), the following compounds are preferred.

(52) α-substituted carboxylic acid derivatives, pharmaceutically acceptable esters thereof, or pharmaceutically acceptable amides or pharmaceutically acceptable salts thereof, wherein

R ₁ , R ₂ and R ₃ are the same or different, and represent (i) hydrogen atom, (ii) C ₁ -C ₄ alkyl group, (iii) phenyl group (may have 1 substituted moiety α ₁ ), (iv) benzene C ₁ -C ₂ alkyl (can have 1-3 substituents α ₁ on phenyl) or (v) C ₁ -C ₂ alkylsulfonyl,

A represents =CH-group,

B represents an oxygen atom,

W ₁ represents a C ₁ -C ₄ alkylene group,

W ₂ represents a C ₁ -C ₄ alkylene group,

X represents (i) hydrogen atom, (ii) C ₁ -C ₂ alkyl group, (iii) halogen atom, (iv) hydroxyl group, (v) C ₁ -C ₂ aliphatic acyl group or (vi) amino group,

Y represents an oxygen atom or an S(O)p group (p represents an integer of 0-2 in the formula),

Z ₂ represents a 5- or 6-membered saturated heterocyclic group (may have 1-5 substituents α ₁ ) or phenyl (has 1-3 substituents α ₂ ),

The substituent moiety _α1 represents (i) C ₁ -C ₄ alkyl, (ii) halogen atom, (iii) hydroxyl, (iv) adamantyl, (v) benzoyl, (vi) amino (may have 1 substitution moiety β) or (vii) carboxyl,

The substituent moiety α ₂ represents a C ₆ -C ₁₀ cycloalkyl group,

The substituent β represents (i) C ₁ -C ₄ alkyl, (ii) a halogen atom or (iii) phenylaminocarbonyl (1-3 substituents γ may be present on the phenyl group),

The substituent γ represents a trifluoromethyl group or a halogen atom.

(53) α-substituted carboxylic acid derivatives, pharmaceutically acceptable esters thereof, or pharmaceutically acceptable amides or pharmaceutically acceptable salts thereof, wherein

R ₁ , R ₂ and R ₃ are the same or different, and represent (i) hydrogen atom, (ii) C ₁ -C ₄ alkyl group or (iii) benzyl group (may have 1 substituent moiety α ₁ on the phenyl group) ,

A represents =CH-group,

B represents an oxygen atom,

W ₁ represents a C ₁ -C ₂ alkylene group,

W ₂ represents a C ₁ -C ₂ alkylene group,

X represents a hydrogen atom,

Y represents an oxygen atom or an S(O)p group (p represents an integer of 0-2 in the formula),

Z ₂ represents a tetrahydropyranyl group (may have 1-5 substituent moieties α ₁ ),

The substituent moiety _α1 represents a hydroxyl group or a carboxyl group.

(54) α-substituted carboxylic acid derivatives, their pharmaceutically acceptable esters, or their pharmaceutically acceptable amides or their pharmaceutically acceptable salts, wherein

R ₁ , R ₂ and R ₃ are the same or different, and represent (i) hydrogen atom, (ii) C ₁ -C ₄ alkyl group or (iii) benzyl group (may have 1 substituent moiety α ₁ on the phenyl group) ,

A represents =CH-group,

B represents an oxygen atom,

W ₁ represents a C ₁ -C ₂ alkylene group,

W ₂ represents a C ₁ -C ₂ alkylene group,

X represents a hydrogen atom,

Y represents an oxygen atom or an S(O)p group (p represents an integer of 0-2 in the formula),

Z ₂ represents phenyl (having 1 substituent moiety α ₂ ),

The substituent moiety _α1 represents a halogen atom or an adamantyl group,

The substituent moiety _α2 represents an adamantyl group.

In addition, among the α-substituted carboxylic acid derivatives having the above general formula (III), preferably:

(55) Z ₃ represents (i) C ₁ -C ₄ alkyl, (ii) C ₆ -C ₁₀ aryl (may have 1-3 substituted moieties α ₁ ) or (iii) C ₃ -C ₁₀ cycloalkane α-substituted carboxylic acid derivatives, their pharmaceutically acceptable esters, or their pharmaceutically acceptable amides or their pharmaceutically acceptable salts.

(56) Z ₃ represents an α-substituted carboxylic acid derivative of C ₁ -C ₄ alkyl, phenyl (may have 1-3 substituted moieties α ₁ ) or C ₃ -C ₁₀ cycloalkyl, which is pharmaceutically acceptable Acceptable esters, or pharmaceutically acceptable amides thereof, or pharmaceutically acceptable salts thereof.

(57) Z ₃ represents an α-substituted carboxylic acid derivative of phenyl (which may have 1-3 substituted moieties α ₁ ), its pharmaceutically acceptable ester, or its pharmaceutically acceptable amide, or its pharmaceutically acceptable acceptable salt.

Moreover, among the α-substituted carboxylic acid derivatives having the above general formula (III), it is preferred that R ₁ , R ₂ and R ₃ selected from (1)-(8) be selected from (9) or (10) A, B selected from (11) or (12), W ₁ selected from (13)-(16), W ₂ selected from (17)-(20), selected from (21)-(23) X, Z ₃ selected from (55)-(57), α ₁ selected from (28)-(36), β selected from (37)-(39), selected from (40)-(42) The compound formed by the combination of γ.

For example, among the α-substituted carboxylic acid derivatives having the above general formula (III), the following compounds are preferred.

(58) α-substituted carboxylic acid derivatives, their pharmaceutically acceptable esters, or their pharmaceutically acceptable amides or their pharmaceutically acceptable salts, wherein

R ₁ , R ₂ and R ₃ are the same or different, and represent (i) hydrogen atom, (ii) C ₁ -C ₄ alkyl group or (iii) benzyl group (may have 1 substituent moiety α ₁ on the phenyl group) ,

A represents =CH-group,

B represents an oxygen atom,

W ₁ represents a C ₁ -C ₂ alkylene group,

W ₂ represents a C ₁ -C ₂ alkylene group,

X represents a hydrogen atom,

Y represents an oxygen atom or an S(O)p group (p represents an integer of 0-2 in the formula),

Z ₃ represents (i) C ₁ -C ₄ alkyl; (ii) C ₆ -C ₁₀ aryl (may have 1-3 substituted moieties α ₁ ) or (iii) C ₃ -C ₁₀ cycloalkyl,

The substituent moiety _α1 represents (i) a C ₁ -C ₄ alkyl group, (ii) a halogen atom, (iii) a hydroxyl group or (iv) an adamantyl group.

(59) α-substituted carboxylic acid derivatives, pharmaceutically acceptable esters thereof, or pharmaceutically acceptable amides or pharmaceutically acceptable salts thereof, wherein

R ₁ represents a C ₁ -C ₂ alkyl group, R ₂ represents a hydrogen atom, R ₃ represents a C ₁ -C ₄ alkyl group or a phenyl C ₁ -C ₄ alkyl group (the phenyl group may have one substituent α ₁ ),

A represents =CH-group,

B represents an oxygen atom,

W ₁ represents a methylene group,

W ₂ represents a methylene group,

X represents a hydrogen atom,

Y represents an oxygen atom or an S(O)p group (p represents an integer of 0-2 in the formula),

Z ₃ represents phenyl (may have 1-3 substituted moieties α ₁ ),

The substituent moiety α ₁ represents C ₁ -C ₄ alkyl or hydroxyl.

In addition, among the α-substituted carboxylic acid derivatives having the above general formula (IV), preferably:

(60) R ₄ represents an α-substituted carboxylic acid derivative of C ₁ -C ₄ alkyl or phenyl (may have 1-3 substituted moieties α ₁ ), its pharmaceutically acceptable esters, or its pharmaceutically acceptable An acceptable amide or a pharmaceutically acceptable salt thereof.

(61) R ₄ represents an α-substituted carboxylic acid derivative of phenyl (which may have one substituted moiety α ₁ ), its pharmaceutically acceptable ester, or its pharmaceutically acceptable amide, or its pharmaceutically acceptable of salt.

(62) Z ₄ represents (i) C ₁ -C ₄ alkoxy, (ii) _C 1-C ₄ alkylthio, (iii) C ₆ -C ₁₀ aryloxy (can have 1-3 substituted moieties α ₁ ), (iv) benzyloxy (may have 1-3 substituents α ₁ on the phenyl group), (v) C ₆ -C ₁₀ arylthio (may have 1-3 substituents α ₁ ) or (vi) α-substituted carboxylic acid derivatives of benzylthio (which may have 1-5 substituent moieties α ₁ on the phenyl group), their pharmaceutically acceptable esters, or their pharmaceutically acceptable amides or its pharmaceutically acceptable salt.

(63) Z ₄ represents (i) C ₁ -C ₄ alkoxy, (ii) C ₁ -C ₂ alkylthio, (iii) phenoxy (may have 1-3 substituted moieties α ₁ ) or ( iv) α-substituted carboxylic acid derivatives of phenylthio (may have 1-3 substituted moieties α ₁ ), their pharmaceutically acceptable esters, or their pharmaceutically acceptable amides, or their pharmaceutically acceptable Salt.

(64) Z ₄ represents an α-substituted carboxylic acid derivative of C ₁ -C ₂ alkoxy or phenoxy (which may have 1-3 substituted moieties α ₁ ), its pharmaceutically acceptable esters, or A pharmaceutically acceptable amide or a pharmaceutically acceptable salt thereof.

(65) Z ₄ represents a C ₁ -C ₂ alkoxy α-substituted carboxylic acid derivative, a pharmaceutically acceptable ester thereof, or a pharmaceutically acceptable amide or a pharmaceutically acceptable salt thereof.

(66) Z ₄ represents an α-substituted carboxylic acid derivative of phenoxy (which may have 1-3 substituted moieties α ₁ ), its pharmaceutically acceptable ester, or its pharmaceutically acceptable amide, or its pharmaceutical acceptable salt.

Moreover, among the α-substituted carboxylic acid derivatives having the above general formula (IV), it is preferred that R ₁ , R ₂ and R ₃ selected from (1)-(8) be selected from (60) or (61) R ₄ , A selected from (9) or (10), B selected from (11) or (12), W ₁ selected from (13)-(16), selected from (17)-(20) W ₂ selected from (21)-(23), X selected from (62)-(66), Z ₄ selected from (62)-(66), α ₁ selected from (28)-(36), selected from (37)-(39) ) of β, selected from the compounds formed by the combination of (40)-(42) γ.

For example, among the α-substituted carboxylic acid derivatives having the above general formula (IV), the following compounds are preferred.

(67) α-substituted carboxylic acid derivatives, pharmaceutically acceptable esters thereof, or pharmaceutically acceptable amides or pharmaceutically acceptable salts thereof, wherein

R ₁ , R ₂ and R ₃ are the same or different, and represent (i) hydrogen atom, (ii) C ₁ -C ₄ alkyl group or (iii) benzyl group (may have 1 substituent moiety α ₁ on the phenyl group) ,

R ₄ represents C ₁ -C ₄ alkyl or phenyl (may have 1-3 substituents α ₁ ),

A represents =CH-group,

B represents an oxygen atom,

W ₁ represents a C ₁ -C ₂ alkylene group,

W ₂ represents a C ₁ -C ₂ alkylene group,

X represents (i) hydrogen atom, (ii) C ₁ -C ₂ alkyl group, (iii) halogen atom, (iv) hydroxyl group, (v) C ₁ -C ₂ aliphatic acyl group or (vi) amino group,

Z ₄ represents (i) C ₁ -C ₄ alkoxy, (ii) C ₁ -C ₂ alkylthio, (iii) phenoxy (may have 1-3 substituted moieties α ₁ ) or (iv) benzene Thio (may have 1-3 substituent moieties α ₁ ),

The substituent moiety _α1 represents (i) C ₁ -C ₄ alkyl, (ii) halogen atom, (iii) hydroxyl, (iv) adamantyl, (v) benzoyl, (vi) amino (may have 1 substitution moiety β) or (vii) carboxyl,

The substituent β represents (i) C ₁ -C ₄ alkyl, (ii) a halogen atom or (iii) phenylaminocarbonyl (1-3 substituents γ may be present on the phenyl group),

The substituent γ represents a trifluoromethyl group or a halogen atom.

(68) α-substituted carboxylic acid derivatives, pharmaceutically acceptable esters thereof, or pharmaceutically acceptable amides or pharmaceutically acceptable salts thereof, wherein

R ₁ represents a C ₁ -C ₂ alkyl group, R ₂ represents a hydrogen atom, R ₃ represents a hydrogen atom,

R ₄ represents phenyl (may have one substituent α ₁ ),

A represents =CH-group,

B represents an oxygen atom,

W ₁ represents a methylene group,

W ₂ represents a methylene group,

X represents a hydrogen atom,

Z ₄ represents C ₁ -C ₂ alkoxy,

The substituent moiety _α1 represents a benzoyl group.

(69) α-substituted carboxylic acid derivatives, pharmaceutically acceptable esters thereof, or pharmaceutically acceptable amides or pharmaceutically acceptable salts thereof, wherein

R ₁ represents a C ₁ -C ₂ alkyl group, R ₂ represents a hydrogen atom, R ₃ represents a hydrogen atom,

R ₄ represents phenyl (may have one substituent α ₁ ),

A represents =CH-group,

B represents an oxygen atom,

W ₁ represents a methylene group,

W ₂ represents a methylene group,

X represents a hydrogen atom,

Z ₄ represents phenoxy (may have 1-3 substituent moieties α ₁ ),

The substituent moiety _α1 represents a C ₁ -C ₄ alkyl, benzoyl or amino group (may have 1 substituent moiety β),

The substituent β represents a phenylaminocarbonyl group (one substituent γ may be present on the phenyl group),

The substituent moiety γ represents a trifluoromethyl group.

Examples of the α-substituted carboxylic acid derivatives of the present invention include the compounds listed in Table 1 to Table 5, but the present invention is not limited to these compounds. The compounds in Table 1 to Table 5 have the structural formulas of Formulas I-1 to I-5, respectively. The abbreviations in the table are as follows.

Ac: Acetyl

Ada: King Kong

Boz: Benzoyl

Bu: butyl

iBu: isobutyl

sBu: sec-butyl

tBu: tert-butyl

Bz: benzyl

Byr: butyryl

iByr: isobutyryl

Car: Carbamoyl

Et: ethyl

GlcA: β-D-glucopiran ulanosil okish

(β-D-glucopyranuranosyloxy)

Hx: Hexyl

iHx: isohexyl

sHx: sec-hexyl

cHx: cyclohexyl

Hynyl: hexanoyl

Imid: imidazolyl

Me: methyl

Mor: Morpholinyl

Nic: Nicotinyl

iNic: Isonicotinoyl

Np: naphthyl

Ph: phenyl

Pip: 1-piperidinyl

Pipra: piperazinyl

Pn: pentyl

cPn: cyclopentyl

cPnc: cyclopentylcarbonyl

Pr: Propyl

cPr: cyclopropyl

iPr: isopropyl

Pm: Propionyl

Pyr: pyridyl

Pyrd: pyrrolidinyl

TioMor: Thiomorpholino

Tos: p-toluenesulfonyl

Va: pentanoyl

E.C.No.: Example compound number

(式中R₁、R₂、R₃、A、B、W₁、W₂、X、Y和Z₁同上定义，m和n分别表示1-8的整数。)E.C.No. B  X    Y  Z           R₁   R₂  R₃      m    n1-1     O  H    O  4-AdaPhO    Me    H    4-FBz    1    11-2     O  H    O  4-AdaPhO    Me    H    4-FBz    1    01-3     O  H    O  4-AdaPhO    Me    H    4-FBz    1    21-4     O  H    O  4-AdaPhO    Me    H    4-FBz    1    31-5     O  H    O  4-AdaPhO    Me    H    4-FBz    1    41-6     O  H    O  4-AdaPhO    Me    H    4-FBz    1    51-7     O  H    O  4-AdaPhO    Me    H    4-FBz    1    61-8     O  H    O  4-AdaPhO    Me    H    4-FBz    1    71-9     O  H    O  4-AdaPhO    Me    H    4-FBz    1    81-10    O  H    O  4-AdaPhO    Me    H    4-FBz    2    11-11    O  H    O  4-AdaPhO    Me    H    4-FBz    3    11-12    O  H    O  4-AdaPhO    Me    H    4-FBz    4    11-13    O  H    O  4-AdaPhO    Me     H    4-FBz    5    11-14    O  H    O  4-AdaPhO    Me     H    4-FBz    6    11-15    O  H    O  4-AdaPhO    Me     H    4-FBz    7    11-16    O  H    O  4-AdaPhO    Me     H    4-FBz    8    11-17    O  H    S  4-AdaPhO    Me     H    H        1    11-18    O  H    S  4-AdaPhO    Me     H    Me       1    11-19    O  H    S  4-AdaPhO    Me     H    Et       1    11-20    O  H    S  4-AdaPhO    Me     H    Bu       1    11-21    O  H    S  4-AdaPhO    Me     H    Ph       1    11-22    O  H    S  4-AdaPhO    Me     H    Bz       1    11-23    O  H    S  4-AdaPhO    Me     H    4-ClBz   1    11-24    S  H    S  4-AdaPhO    Me     H    4-FBz    1    11-25    O  H    O  4-AdaPhO    Me     H    4-FBz    1    11-26    O  H    S  4-AdaPhO    4-FBz  H    4-FBz    1    11-27    O  H    S  4-AdaPhO    Et     H    4-FBz    1    11-28    O  H    S  4-AdaPhO    Pr     H    4-FBz    1    11-29    O  H    S  4-AdaPhO    iPr    H    4-FBz    1    11-30    O  H    S  4-AdaPhO    Bu     H    4-FBz    1    11-31    O  H    S  4-AdaPhO    iBu    H    4-FBz    1    11-32    O  H    S  4-AdaPhO    sBu    H    4-FBz    1    11-33    O  H    S  4-AdaPhO    Pn    H        4-FBz    1    11-34    O  H    S  4-AdaPhO    Hx    H        4-FBz    1    11-35    O  H    S  4-AdaPhO    Ph    H        4-FBz    1    11-36    O  H    S  4-AdaPhO    Bz    H        4-FBz    1    11-37    O  H    S  4-AdaPhO    Me    Me       4-FBz    1    11-38    O  H    S  4-AdaPhO    Me    Et       4-FBz    1    11-39    O  H    S  4-AdaPhO    Me    Pr       4-FBz    1    11-40    O  H    S  4-AdaPhO    Me    iPr      4-FBz    1    11-41    O  H    S  4-AdaPhO    Me    Bu       4-FBz    1    11-42    O  H    S  4-AdaPhO    Me    iBu      4-FBz    1    11-43    O  H    S  4-AdaPhO    Me    sBu      4-FBz    1    11-44    O  H    S  4-AdaPhO    Me    Pn       4-FBz    1    11-45    O  H    S  4-AdaPhO    Me    Hx       4-FBz    1    11-46    O  H    S  4-AdaPhO    Me    Ph       4-FBz    1    11-47    O  H    S  4-AdaPhO    Me    4-FPh    4-FBz    1    11-48    O  H    S  4-AdaPhO    Me    3-CF₃Ph 4-FBz    1    11-49    O  H    S  4-AdaPhO    Me    3-MeOPh  4-FBz    1    11-50    O  H    S  4-AdaPhO    Me    2-MePh   4-FBz    1    11-51    O  H    S  4-AdaPhO    Me    4-CNPh   4-FBz    1    11-52    O  H    S  4-AdaPhO    Me    Bz       4-FBz    1    11-53    O  H       S  4-AdaPhO    Me    3-FBz         4-FBz    1    11-54    O  H       S  4-AdaPhO    Me    2-CF₃Bz      4-FBz    1    11-55    O  H       S  4-AdaPhO    Me    3，5-二MeOBz  4-FBz    1    11-56    O  H       S  4-AdaPhO    Me    4-ClBz        4-FBz    1    11-57    O  Cl      S  4-AdaPhO    Me    H             4-FBz    1    11-58    O  F       S  4-AdaPhO    Me    H             4-FBz    1    11-59    O  Br      S  4-AdaPhO    Me    H             4-FBz    1    11-60    O  Me      S  4-AdaPhO    Me    H             4-FBz    1    11-61    O  MeO     S  4-AdaPhO    Me    H             4-FBz    1    11-62    O  EtO     S  4-AdaPhO    Me    H             4-FBz    1    11-63    O  iPr     S  4-AdaPhO    Me    H             4-FBz    1    11-64    O  CF₃    S  4-AdaPhO    Me    H             4-FBz    1    11-65    O  HO      S  4-AdaPhO    Me    H             4-FBz    1    11-66    O  EtO     S  4-AdaPhO    Me    H             4-FBz    1    11-67    O  tBu     S  4-AdaPhO    Me    H             4-FBz    1    11-68    O  Ac      S  4-AdaPhO    Me    H             4-FBz    1    11-69    O  Boz     S  4-AdaPhO    Me    H             4-FBz    1    11-70    O  PhAc    S  4-AdaPhO    Me    H             4-FBz    1    11-71    O  cPnc    S  4-AdaPhO    Me    H             4-FBz    1    11-72    O  NH₂    S  4-AdaPhO    Me    H             4-FBz    1    11-73    O  NHAc     S  4-AdaPhO         Me    H     4-FBz    1    11-74    O  NHBoz    S  4-AdaPhO         Me    H     4-FBz    1    11-75    O  NHMe     S  4-AdaPhO         Me    H     4-FBz    1    11-76    O  NHiPr    S  4-AdaPhO         Me    H     4-FBz    1    11-77    O  NHPh     S  4-AdaPhO         Me    H     4-FBz    1    11-78    O  NHBz     S  4-AdaPhO         Me    H     4-FBz    1    11-79    O  NMeEt    S  4-AdaPhO         Me    H     4-FBz    1    11-80    O  NEtPh    S  4-AdaPhO         Me    H     4-FBz    1    11-81    O  NPhBz    S  4-AdaPhO         Me    H     4-FBz    1    11-82    O  Ph       S  4-AdaPhO         Me    H     4-FBz    1    11-83    O  Np       S  4-AdaPhO         Me    H     4-FBz    1    11-84    O  CN       S  4-AdaPhO         Me    H     4-FBz    1    11-85    O  NO₂     S  4-AdaPhO         Me    H     4-FBz    1    11-86    O  H        O  4-HO-3，5-二-    Me    H     4-FBz    1    1[Table 1]

(In the formula, R ₁ , R ₂ , R ₃ , A, B, W ₁ , W ₂ , X, Y and Z ₁ are as defined above, and m and n respectively represent integers from 1 to 8.) ECNo. B X Y Z R ₁ R ₂ R ₃ m n1-1 O HO 4-AdaPhO Me H 4-FBz 1 11-2 O HO 4-AdaPhO Me H 4-FBz 1 01-3 O HO 4-AdaPhO Me H 4-FBz 1 21-4 O HO 4-AdaPhO Me H 4-FBz 1 31-5 O H O 4-AdaPhO Me H 4-FBz 1 41-6 O H O 4-AdaPhO Me H 4-FBz 1 51-7 O H O 4-AdaPhO Me H 4-FBz 1 61-8 O HO 4-AdaPhO Me H 4-FBz 1 71-9 O HO 4-AdaPhO Me H 4-FBz 1 81-10 O HO 4-AdaPhO Me H 4-FBz 2 11-11 O HO 4-AdaPhO Me H 4-FBz 3 11-12 O HO 4 -AdaPhO Me H 4-FBz 4 11-13 O HO 4-AdaPhO Me H 4-FBz 5 11-14 O HO 4-AdaPhO Me H 4-FBz 6 11-15 O HO 4-AdaPhO Me H 4-FBz 7 11-16 O H O 4-AdaPhO Me H 4-FBz 8 11-17 O H S 4-AdaPhO Me H H 1 11-18 O H S 4-AdaPhO Me H Me 1 11-19 O H S 4-AdaPhO Me H Et 1 11-20 O H S 4-AdaPhO Me H Bu 1 11-21 O H S 4-AdaPhO Me H Ph 1 11-22 O H S 4-AdaPhO Me H Bz 1 11-23 O H S 4-AdaPhO Me H 4-ClBz 1 11-24 S H S 4-AdaPhO Me H 4-FBz 1 11-25 O H O 4-AdaPhO Me H 4-FBz 1 11-26 O H S 4-AdaPhO 4-FBz H 4-FBz 1 11-27 O H S 4-AdaPhO Et H 4-FBz 1 11-28 O H S 4-AdaPhO Pr H 4-FBz 1 11-29 O H S 4-AdaPhO iPr H 4-FBz 1 11-30 O H S 4-AdaPhO Bu H 4-FBz 1 11-31 O H S 4-AdaPhO iBu H 4-FBz 1 11-32 O H S 4- AdaPhO sBu H 4-FBz 1 11-33 O H S 4-AdaPhO Pn H 4-FBz 1 11-34 O H S 4-AdaPhO Hx H 4-FBz 1 11-35 O H S 4-AdaPhO Ph H 4-FBz 1 11-36 O H S 4-AdaPhO Bz H 4-FBz 1 11-37 O H S 4-AdaPhO Me 4-FBz 1 11-38 O H S 4-AdaPhO Me Et 4-FBz 1 11-39 O H S 4-AdaPhO Me Pr 4-FBz 1 11- 40 O H S 4-AdaPhO Me iPr 4-FBz 1 11-41 O H S 4-AdaPhO Me Bu 4-FBz 1 11-42 O H S 4-AdaPhO Me iBu 4-FBz 1 11-43 O H S 4-AdaPhO Me sBu 4-FBz 1 11-44 O H S 4-AdaPhO Me Pn 4-FBz 1 11-45 O H S 4-AdaPhO Me Hx 4-FBz 1 11-46 O H S 4-AdaPhO Me Ph 4-FBz 1 11-47 O H S 4-AdaPhO Me 4-FPh 4-FBz 1 11-48 O H S 4-AdaPhO Me 3-CF ₃ Ph 4-FBz 1 11-49 O H S 4-AdaPhO Me 3-MeOPh 4-FBz 1 11-50 O H S 4-AdaPhO Me 2-MePh 4-FBz 1 11-51 O H S 4-AdaPhO Me 4-CNPh 4-FBz 1 11-52 O H S 4-AdaPhO Me Bz 4-FBz 1 11-53 O H S 4-AdaPhO Me 3-FBz 4-FBz 1 11-54 O H S 4- AdaPhO Me 2-CF ₃ Bz 4-FBz 1 11-55 O H S 4-AdaPhO Me 3,5-diMeOBz 4-FBz 1 11-56 O H S 4-AdaPhO Me 4-ClBz 4-FBz 1 11-57 O Cl S 4-AdaPhO Me H 4-FBz 1 11-58 O F S 4-AdaPhO Me H 4-FBz 1 11-59 O Br S 4-AdaPhO Me H 4-FBz 1 11-60 O Me S 4-AdaPhO Me H 4- FBz 1 11-61 O MeO S 4-AdaPhO Me H 4-FBz 1 11-62 O EtO S 4-AdaPhO Me H 4-FBz 1 11-63 O iPr S 4-AdaPhO Me H 4-FBz 1 11-64 O CF ₃ S 4-AdaPhO Me H 4-FBz 1 11-65 O HOS 4-AdaPhO Me H 4-FBz 1 11-66 O EtO S 4-AdaPhO Me H 4-FBz 1 11-67 O tBu S 4 -AdaPhO Me H 4-FBz 1 11-68 O Ac S 4-AdaPhO Me H 4-FBz 1 11-69 O Boz S 4-AdaPhO Me H 4-FBz 1 11-70 O PhAc S 4-AdaPhO Me H 4 -FBz 1 11-71 O cPnc S 4-AdaPhO Me H 4-FBz 1 11-72 O NH ₂ S 4-AdaPhO Me H 4-FBz 1 11-73 O NHAc S 4-AdaPhO Me H 4-FBz 1 11 -74 O NHBoz S 4-AdaPhO Me H 4-FBz 1 11-75 O NHMe S 4-AdaPhO Me H 4-FBz 1 11-76 O NHiPr S 4-AdaPhO Me H 4-FBz 1 11-77 O NHPh S 4-AdaPhO Me H 4-FBz 1 11-78 O NHBz S 4-AdaPhO Me H 4-FBz 1 11-79 O NMeEt S 4-AdaPhO Me H 4-FBz 1 11-80 O NEtPh S 4-AdaPhO Me H 4-FBz 1 11-81 O NPhBz S 4-AdaPhO Me H 4-FBz 1 11-82 O Ph S 4-AdaPhO Me H 4-FBz 1 11-83 O Np S 4-AdaPhO Me H 4-FBz 1 11 -84 O CN S 4-AdaPhO Me H 4-FBz 1 11-85 O NO ₂ S 4-AdaPhO Me H 4-FBz 1 11-86 O H O 4-HO-3,5-di-Me H 4-FBz 1 1

tBuPhS1-87 O H O 4-HO-3,5-Two- Me H H H 1 1

tBuPhS1-88 O H S 4-HO-3,5-Two- Me H Me 1 1

tBuPhS1-89 O H S 4-HO-3,5-Two- Me H Et 1 1

tBuPhS1-90 O H S 4-HO-3,5-Two- Me H Hx 1 1

tBuPhS1-91 O H S 4-HO-3,5-Two- Me H Bz 1 1

tBuPhS1-92 O H O 4-HO-3,5-Two- Me H Ph 1 1

tBuPhS1-93 O H O 4-HO-3,5-Two- Me H 4-FBz 1 0

tBuPhS1-94 O H O 4-HO-3,5-Two- Me H 4-FBz 1 2

tBuPhS1-95 O H O 4-HO-3,5-Two- Me H 4-FBz 1 3

tBuPhS1-96 O H O 4-HO-3,5-Two- Me H 4-FBz 1 4

tBuPhS1-97 O H O 4-HO-3,5-Two- Me H 4-FBz 1 5

tBuPhS1-98 O H O 4-HO-3,5-Two- Me H 4-FBz 1 6

tBuPhS1-99 O H O 4-HO-3,5-Two- Me H 4-FBz 1 7

tBuPhS1-100 O H O 4-HO-3,5-Two- Me H 4-FBz 1 8

tBuPhS1-101 O H O 4-HO-3,5-Two- Me H 4-FBz 2 1

tBuPhS1-102 O H O 4-HO-3,5-Two- Me H 4-FBz 3 1

tBuPhS1-103 O H O 4-HO-3,5-Two- Me H 4-FBz 4 1

tBuPhS1-104 O H O 4-HO-3,5-Two- Me H 4-FBz 5 1

tBuPhS1-105 O H O 4-HO-3,5-Two- Me H 4-FBz 6 1

tBuPhS1-106 O H O 4-HO-3,5-Two- Me H 4-FBz 7 1

tBuPhS1-107 O H O 4-HO-3,5-Two- Me H 4-FBz 8 1

tBuPhS1-108 S H S 4-HO-3,5-Two- Me H 4-FBz 1 1

tBuPhS1-109 O H O 4-HO-3,5-Two- Me H 4-FBz 1 1

BuPhS1-110 O H S 4-HO-3,5-Two- Me H 4-FBz 1 1

tBuPhO1-111 O H S 4-HO-3,5-Two- Et H 4-FBz 1 1

tBuPhS1-112 O H S 4-HO-3,5-Two- Pr H 4-FBz 1 1

tBuPhS1-113 O H S 4-HO-3,5-two- iPr H 4-FBz 1 1

tBuPhS1-114 O H S 4-HO-3,5-Two- Bu H 4-FBz 1 1

tBuPhS1-115 O H S 4-HO-3,5-two- iBu H 4-FBz 1 1

tBuPhS1-116 O H S 4-HO-3,5-two- sBu H 4-FBz 1 1

tBuPhS1-117 O H S 4-HO-3,5-Two- Pn H 4-FBz 1 1

tBuPhS1-118 O H S 4-HO-3,5-two- Hx H 4-FBz 1 1

tBuPhS1-119 O H S 4-HO-3,5-Two- Ph H 4-FBz 1 1

tBuPhS1-120 O H S 4-HO-3,5-Two- Bz H 4-FBz 1 1

tBuPhS1-121 O H S 4-HO-3,5-Two- Me Me 4-FBz 1 1

tBuPhS1-122 O H S 4-HO-3,5-Two- Me Et 4-FBz 1 1

tBuPhS1-123 O H S 4-HO-3,5-Two- Me Pr 4-FBz 1 1

tBuPhS1-124 O H S 4-HO-3,5-Two- Me iPr 4-FBz 1 1

tBuPhS1-125 O H S 4-HO-3,5-Two- Me Bu Bu 4-FBz 1 1

tBuPhS1-126 O H S 4-HO-3,5-Two- Me iBu 4-FBz 1 1

tBuPhS1-127 O H S 4-HO-3,5-Two- Me sBu 4-FBz 1 1

tBuPhS1-128 O H S 4-HO-3,5-Two- Me Pn 4-FBz 1 1

tBuPhS1-129 O H S 4-HO-3,5-Two- Me Hx 4-FBz 1 1

tBuPhS1-130 O H S 4-HO-3,5-Two- Me Ph Ph 4-FBz 1 1

tBuPhS1-131 O H S 4-HO-3,5-Two- Me 4-FPh 4-FBz 1 1

tBuPhS1-132 OHS 4-HO-3,5-di-Me 3-CF ₃ Ph 4-FBz 1 1

tBuPhS1-133 O H S 4-HO-3,5-Two- Me 3-MeOPh 4-FBz 1 1

tBuPhS1-134 O H S 4-HO-3,5-Two- Me 2-MePh 4-FBz 1 1

tBuPhS1-135 O H S 4-HO-3,5-Two- Me 4-CNPh 4-FBz 1 1

tBuPhS1-136 O H S 4-HO-3,5-Two- Me Bz 4-FBz 1 1

tBuPhS1-137 O H S 4-HO-3,5-Two- Me 3-FBz 4-FBz 1 1

tBuPhS1-138 O H S 4-HO-3,5-di-Me 2-CF ₃ Bz 4-FBz 1 1

tBuPhS1-139 O H S 4-HO-3,5-Di-Me 3,5-DiMeOBz 4-FBz 1 1

tBuPhS1-140 O H S 4-HO-3,5-Two- Me 4-ClBz 4-FBz 1 1

tBuPhS1-141 O Cl S 4-HO-3,5-Two- Me H H 4-FBz 1 1

tBuPhS1-142 O F S 4-HO-3,5-Two- Me H H 4-FBz 1 1

tBuPhS1-143 O Br S 4-HO-3,5-Two- Me H 4-FBz 1 1

tBuPhS1-144 O Me S 4-HO-3,5-Two- Me H 4-FBz 1 1

tBuPhS1-145 O MeO S 4-HO-3,5-Two- Me H 4-FBz 1 1

tBuPhS1-146 O EtO S 4-HO-3,5-Two- Me H 4-FBz 1 1

tBuPhS1-147 O iPr S 4-HO-3,5-Two- Me H 4-FBz 1 1

tBuPhS1-148 O CF ₃ S 4-HO-3,5-di-Me H 4-FBz 1 1

tBuPhS1-149 O HO S 4-HO-3,5-Two- Me H 4-FBz 1 1

tBuPhS1-150 O EtO S 4-HO-3,5-Two- Me H 4-FBz 1 1

tBuPhS1-151 O tBu S 4-HO-3,5-Two- Me H 4-FBz 1 1

tBuPhS1-152 O Ac S 4-HO-3,5-Two- Me H 4-FBz 1 1

tBuPhS1-153 O Boz S 4-HO-3,5-Two- Me H 4-FBz 1 1

tBuPhS1-154 O PhAc S 4-HO-3,5-Two- Me H 4-FBz 1 1

tBuPhS1-155 O cPnc S 4-HO-3,5-Two- Me H 4-FBz 1 1

tBuPhS1-156 O NH ₂ S 4-HO-3,5-di-Me H 4-FBz 1 1

tBuPhS1-157 O NHAc S 4-HO-3,5-Two- Me H 4-FBz 1 1

tBuPhS1-158 O NHBoz S 4-HO-3,5-Two- Me H 4-FBz 1 1

tBuPhS1-159 O NHMe S 4-HO-3,5-Two- Me H 4-FBz 1 1

tBuPhS1-160 O NHiPr S 4-HO-3,5-Two- Me H 4-FBz 1 1

tBuPhS1-161 O NHPh S 4-HO-3,5-Two- Me H 4-FBz 1 1

tBuPhS1-162 O NHBz S 4-HO-3,5-Two- Me H 4-FBz 1 1

tBuPhS1-163 O NMeEt S 4-HO-3,5-Two- Me H 4-FBz 1 1

tBuPhS1-164 O NEtPh S 4-HO-3,5-Two- Me H 4-FBz 1 1

tBuPhS1-165 O NPhBz S 4-HO-3,5-Two- Me H 4-FBz 1 1

tBuPhS1-166 O Ph S 4-HO-3,5-Two- Me H 4-FBz 1 1

tBuPhS1-167 O Np S 4-HO-3,5-Two- Me H 4-FBz 1 1

tBuPhS1-168 O CN S 4-HO-3,5-Two- Me H 4-FBz 1 1

tBuPhS1-169 O NO ₂ S 4-HO-3,5-di-Me H 4-FBz 1 1

tBuPhS1-170 O H O 4-HO-2,3,5- Me H H H 1 1

Three MehO1-171 O H O 4-HO-2,3,5- Me H Me 1 1

Three MePhO1-172 O H O 4-HO-2,3,5- Me H Et 1 1

Three MePhO1-173 O H O 4-HO-2,3,5- Me H Bu 1 1

Three MePhO1-174 O H O 4-HO-2,3,5- Me H Ph 1 1

Three MePhO1-175 O H O 4-HO-2,3,5- Me H Bz 1 1

Three MePhO1-176 O H S 4-HO-2,3,5- Me H Bz 1 1

Three MePhO1-177 O H O MeO Me H H 1 11-178 O H O MeO Me H Me 1 11-179 O H O MeO Me H Et 1 11-180 O H O MeO Me H Pr 1 11-181 O H O MeO Me H iPr 1 11-182 O H O MeO Me H Pn 1 11-183 O H O MeO Me H Hx 1 11-184 O H O MeO Me H Bz 1 11-185 O H O MeO Me H 4-FBz 1 11-186 O H O MeO Me H 3-CIBz 1 11-187 O H O MeO Me H Ph 1 11-188 O H O EtO Me H Bz 1 11-189 O H O PrO Me H Bz 1 11-190 O H O iPrO Me H Bz 1 11-191 O H O BuO Me H Bz 1 11-192 O H O iBuO Me H Bz 1 11- 193 O H O sBuO Me H Bz 1 11-194 O H O tBuO Me H Bz 1 11-195 O H O PnO Me H Bz 1 11-196 O H O HxO Me H Bz 1 11-197 O H O PhO Me H Bz 1 11-198 O H O 4-ClPhO Me H Bz 1 11-199 O HO 4-FPhO Me H Bz 1 11-200 O HO 2-FPhO Me H Bz 1 11-201 O HO 3-FPhO Me H Bz 1 11-202 O HO 4-CF ₃ PhO Me H Bz 1 11-203 O H O 3-CF ₃ PhO Me H Bz 1 11-204 O H O 4-MeOPhO Me H Bz 1 11-205 O H O 4-MePhO Me H Bz 1 11-206 O H O 4-PhPhO Me H Bz 1 11-207 O H O 3-HOPhO Me H Bz 1 11-208 O HO 3-AcPhO Me H Bz 1 11-209 O HO 4-cPrPhO Me H Bz 1 11-210 O HO 4-Me ₂ NPhO Me H Bz 1 11-211 O HO 4-CNPhO Me H Bz 1 11-212 O H O 4-NO ₂ PhO Me H Bz 1 11-213 O H O Me H Bz 1 11-214 O H O Et Me H Bz 1 11-215 O H O tBu Me H Bz 1 11-216 O H O Hx Me H Bz 1 11-217 O H O Ph Me H Bz 1 11-218 O H O Np Me H Bz 1 11-219 O H O 4-MeOPh Me H Bz 1 11-220 O H O Bz Me H Bz 1 11-221 O H O 4-CF ₃ Bz Me H Bz 1 11-222 O H O MeS Me H Bz 1 11-223 O H O PhS Me H Bz 1 11-224 O H O BzS Me H Bz 1 11-225 O HO 4-FPhS Me H Bz 1 11-226 O HO 4-CF ₃ PhS Me H Bz 1 11-227 O H O 4-FBzS Me H Bz 1 11-228 O H O F Me H Bz 1 11-229 O H O Cl Me H Bz 1 11-230 O H O Br Me H Bz 1 11-231 O H O 2-PyrS Me H Bz 1 11-232 O HO 3-PyrS Me H 4-FBz 1 11-233 O HO 4-PyrS Me H 4-CF ₃ Bz 1 11-234 O HO 2-PyrO Me H 3-MeOBz 1 11-235 O HO 3-PyrO Me H Bz 1 11-236 O H O 4-PyrO Me H Bz 1 11-237 O H O cPrS Me H Bz 1 11-238 O H O cHxS Me H Bz 1 11-239 O H O NH ₂ Me H Bz 1 11-240 O H O NHMe Me H Bz 1 11-241 O H O NMeEt Me H Bz 1 11-242 O H O NHAc Me H Bz 1 11-243 O H O NHPh Me H Bz 1 11-244 O H O NHBz Me H Bz 1 11-245 O H O NH Boz Me H Bz 1 11-246 O H O NMeBoz Me H Bz 1 11-247 O H O NEtBz Me H Bz 1 11-248 O H O NPhBz Me H Bz 1 11-249 O H O NPhBoz Me H Bz 1 11-250 O H O NH(4-FBoz) Me H Bz 1 11-251 O H O NH(3-MeOBoz) Me H Bz 1 11-252 O H O NHBoz Me Me Bz 1 11-253 O H O NHBoz Me Et Bz 1 11-254 O H O NHBoz Me Ph Bz 1 11-255 O H O NHBoz Me Bz Bz 1 1

(式中R₁、R₂、R₃、A、B、W₁、W₂、X、Y、Z₁、m和n同上定义。)E.C.No. B  X    Y   Z           R₁   R₂  R₃      m    n2-1     O  H    S   4-AdaPhO    Me    H    4-FBz    1    12-2     O  H    S   4-AdaPhO    Me    H    4-FBz    1    02-3     O  H    S   4-AdaPhO    Me    H    4-FBz    1    22-4     O  H    S   4-AdaPhO    Me    H    4-FBz    1    32-5     O  H    S   4-AdaPhO    Me    H    4-FBz    1    42-6     O  H    S   4-AdaPhO    Me    H    4-FBz    1    52-7     O  H    S   4-AdaPhO    Me    H    4-FBz    1    62-8     O  H    S   4-AdaPhO    Me    H    4-FBz    1    72-9     O  H    S   4-AdaPhO    Me    H    4-FBz    1    82-10    O  H    S   4-AaPhO     Me    H    4-FBz    2    12-11    O  H    S   4-AdaPhO    Me    H    4-FBz    3    12-12    O  H    S   4-AdaPhO    Me    H    4-FBz    4    12-13    O  H        S  4-AdaPhO    Me  H    4-FBz    5    12-14    O  H        S  4-AdaPhO    Me  H    4-FBz    6    12-15    O  H        S  4-AdaPhO    Me  H    4-FBz    7    12-16    O  H        S  4-AdaPhO    Me  H    4-FBz    8    12-17    O  NPhBz    S  4-AdaPhO    Me  H    4-FBz    1    12-18    O  NPhBz    S  4-AdaPhO    Me  H    4-FBz    1    02-19    O  NPhBz    S  4-AdaPhO    Me  H    4-FBz    1    22-20    O  NPhBz    S  4-AdaPhO    Me  H    4-FBz    1    32-21    O  NPhBz    S  4-AdaPhO    Me  H    4-FBz    1    42-22    O  NPhBz    S  4-AdaPhO    Me  H    4-FBz    1    52-23    O  NPhBz    S  4-AdaPhO    Me  H    4-FBz    1    62-24    O  NPhBz    S  4-AdaPhO    Me  H    4-FBz    1    72-25    O  NPhBz    S  4-AdaPhO    Me  H    4-FBz    1    82-26    O  NPhBz    S  4-AdaPhO    Me  H    4-FBz    2    12-27    O  NPhBz    S  4-AdaPhO    Me  H    4-FBz    3    12-28    O  NPhBz    S  4-AdaPhO    Me  H    4-FBz    4    12-29    O  NPhBz    S  4-AdaPhO    Me  H    4-FBz    5    12-30    O  NPhBz    S  4-AdaPhO    Me  H    4-FBz    6    12-31    O  NPhBz    S  4-AdaPhO    Me  H    4-FBz    7    12-32    O  NPhBz    S  4-AdaPhO    Me  H    4-FBz    8    12-33    O  H        S    4-HO-3，5-二-tBuPhS    Me    H    4-FBz    1    12-34    O  H        S    4-HO-3，5-二-tBuPhS    Me    H    4-FBz    1    02-35    O  H        S    4-HO-3，5-二-tBuPhS    Me    H    4-FBz    1    22-36    O  H        S    4-HO-3，5-二-tBuPhS    Me    H    4-FBz    1    32-37    O  H        S    4-HO-3，5-二-tBuPhS    Me    H    4-FBz    1    42-38    O  H        S    4-HO-3，5-二-tBuPhS    Me    H    4-FBz    1    52-39    O  H        S    4-HO-3，5-二-tBuPhS    Me    H    4-FBz    1    62-40    O  H        S    4-HO-3，5-二-tBuPhS    Me    H    4-FBz    1    72-41    O  H        S    4-HO-3，5-二-tBuPhS    Me    H    4-FBz    1    82-42    O  H        S    4-HO-3，5-二-tBuPhS    Me    H    4-FBz    2    12-43    O  H        S    4-HO-3，5-二-tBuPhS    Me    H    4-FBz    3    12-44    O  H        S    4-HO-3，5-二-tBuPhS    Me    H    4-FBz    4    12-45    O  H        S    4-HO-3，5-二-tBuPhS    Me    H    4-FBz    5    12-46    O  H        S    4-HO-3，5-二-tBuPhS    Me    H    4-FBz    6    12-47    O  H        S    4-HO-3，5-二-tBuPhS    Me    H    4-FBz    7    12-48    O  H        S    4-HO-3，5-二-tBuPhS    Me    H    4-FBz    8    12-49    O  NPhBz    S    4-HO-3，5-二-tBuPhS    Me    H    4-FBz    1    12-50    O  NPhBz    S    4-HO-3，5-二-tBuPhS    Me    H    4-FBz    1    02-51    O  NPhBz    S    4-HO-3，5-二-tBuPhS    Me    H    4-FBz    1    22-52    O  NPhBz    S    4-HO-3，5-二-tBuPhS    Me    H    4-FBz    1    32-53    O  NPhBz    S    4-HO-3，5-二-tBuPhS    Me    H    4-FBz    1    42-54    O  NPhBz    S    4-HO-3，5-二-tBuPhS    Me    H    4-FBz    1    52-55    O  NPhBz    S    4-HO-3，5-二-tBuPhS    Me    H    4-FBz    1    62-56    O  NPhBz    S    4-HO-3，5-二-tBuPhS    Me    H    4-FBz    1    72-57    O  NPhBz    S    4-HO-3，5-二-tBuPhS    Me    H    4-FBz    1    82-58    O  NPhBz    S    4-HO-3，5-二-tBuPhS    Me    H    4-FBz    2    12-59    O  NPhBz    S    4-HO-3，5-二-tBuPhS    Me    H    4-FBz    3    12-60    O  NPhBz    S    4-HO-3，5-二-tBuPhS    Me    H    4-FBz    4    12-61    O  NPhBz    S    4-HO-3，5-二-tBuPhS    Me    H    4-FBz    5    12-62    O  NPhBz    S    4-HO-3，5-二-tBuPhS    Me    H    4-FBz    6    12-63    O  NPhBz    S    4-HO-3，5-二-tBuPhS    Me    H    4-FBz    7    12-64    O  NPhBz    S    4-HO-3，5-二-tBuPhS    Me    H    4-FBz    8    1[Table 2]

(where R ₁ , R ₂ , R ₃ , A, B, W ₁ , W ₂ , X, Y, Z ₁ , m and n are as defined above.) ECNo. B X Y Z R ₁ R ₂ R ₃ m n2-1 O H S 4 -AdaPhO Me H 4-FBz 1 12-2 O H S 4-AdaPhO Me H 4-FBz 1 02-3 O H S 4-AdaPhO Me H 4-FBz 1 22-4 O H S 4-AdaPhO Me H 4-FBz 1 32-5 O H S 4-AdaPhO Me H 4-FBz 1 42-6 O H S 4-AdaPhO Me H 4-FBz 1 52-7 O H S 4-AdaPhO Me H 4-FBz 1 62-8 O H S 4-AdaPhO Me H 4-FBz 1 72 -9 O H S 4-AdaPhO Me H 4-FBz 1 82-10 O H S 4-AaPhO Me H 4-FBz 2 12-11 O H S 4-AdaPhO Me H 4-FBz 3 12-12 O H S 4-AdaPhO Me H 4-FBz 4 12-13 O H S 4-AdaPhO Me H 4-FBz 5 12-14 O H S 4-AdaPhO Me H 4-FBz 6 12-15 O H S 4-AdaPhO Me H 4-FBz 7 12-16 O H S 4-AdaPhO Me H 4 -FBz 8 12-17 O NPhBz S 4-AdaPhO Me H 4-FBz 1 12-18 O NPhBz S 4-AdaPhO Me H 4-FBz 1 02-19 O NPhBz S 4-AdaPhO Me H 4-FBz 1 22- 20 O NPhBz S 4-AdaPhO Me H 4-FBz 1 32-21 O NPhBz S 4-AdaPhO Me H 4-FBz 1 42-22 O NPhBz S 4-AdaPhO Me H 4-FBz 1 52-23 O NPhBz S 4 -AdaPhO Me H 4-FBz 1 62-24 O NPhBz S 4-AdaPhO Me H 4-FBz 1 72-25 O NPhBz S 4-AdaPhO Me H 4-FBz 1 82-26 O NPhBz S 4-AdaPhO Me H 4 -FBz 2 12-27 O NPhBz S 4-AdaPhO Me H 4-FBz 3 12-28 O NPhBz S 4-AdaPhO Me H 4-FBz 4 12-29 O NPhBz S 4-AdaPhO Me H 4-FBz 5 12- 30 O NPhBz S 4-AdaPhO Me H 4-FBz 6 12-31 O NPhBz S 4-AdaPhO Me H 4-FBz 7 12-32 O NPhBz S 4-AdaPhO Me H 4-FBz 8 12-33 O H S 4-HO -3,5-Di-tBuPhS Me H 4-FBz 1 12-34 O H S 4-HO-3,5-Di-tBuPhS Me H 4-FBz 1 02-35 O H S 4-HO-3,5-Di-tBuPhS Me H 4-FBz 1 22-36 O H S 4-HO-3,5-di-tBuPhS Me H 4-FBz 1 32-37 O H S 4-HO-3,5-di-tBuPhS Me H 4-FBz 1 42- 38 O H S 4-HO-3, 5-di-tBuPhS Me H 4-FBz 1 52-39 O H S 4-HO-3, 5-di-tBuPhS Me H 4-FBz 1 62-40 O H S 4-HO-3, 5-Di-tBuPhS Me H 4-FBz 1 72-41 O H S 4-HO-3, 5-Di-tBuPhS Me H 4-FBz 1 82-42 O H S 4-HO-3, 5-Di-tBuPhS Me H 4 -FBz 2 12-43 O H S 4-HO-3,5-di-tBuPhS Me H 4-FBz 3 12-44 O H S 4-HO-3,5-di-tBuPhS Me H 4-FBz 4 12-45 O H S 4 -HO-3,5-di-tBuPhS Me H 4-FBz 5 12-46 O H S 4-HO-3,5-di-tBuPhS Me H 4-FBz 6 12-47 O H S 4-HO-3,5-di -tBuPhS Me H 4-FBz 7 12-48 O H S 4-HO-3,5-di-tBuPhS Me H 4-FBz 8 12-49 O NPhBz S 4-HO-3,5-di-tBuPhS Me H 4- FBz 1 12-50 O NPhBz S 4-HO-3,5-di-tBuPhS Me H 4-FBz 1 02-51 O NPhBz S 4-HO-3,5-di-tBuPhS Me H 4-FBz 1 22- 52 O NPhBz S 4-HO-3,5-di-tBuPhS Me H 4-FBz 1 32-53 O NPhBz S 4-HO-3,5-di-tBuPhS Me H 4-FBz 1 42-54 O NPhBz S 4-HO-3,5-di-tBuPhS Me H 4-FBz 1 52-55 O NPhBz S 4-HO-3,5-di-tBuPhS Me H 4-FBz 1 62-56 O NPhBz S 4-HO- 3,5-di-tBuPhS Me H 4-FBz 1 72-57 O NPhBz S 4-HO-3,5-di-tBuPhS Me H 4-FBz 1 82-58 O NPhBz S 4-HO-3,5- Di-tBuPhS Me H 4-FBz 2 12-59 O NPhBz S 4-HO-3,5-Di-tBuPhS Me H 4-FBz 3 12-60 O NPhBz S 4-HO-3,5-Di-tBuPhS Me H 4-FBz 4 12-61 O NPhBz S 4-HO-3,5-di-tBuPhS Me H 4-FBz 5 12-62 O NPhBz S 4-HO-3,5-di-tBuPhS Me H 4-FBz 6 12-63 O NPhBz S 4-HO-3,5-di-tBuPhS Me H 4-FBz 7 12-64 O NPhBz S 4-HO-3,5-di-tBuPhS Me H 4-FBz 8 1

[table 3] (where R ₁ , R ₂ , R ₃ , R ₄ , A, B, W ₁ , W ₂ , X, Y, Z ₄ , m and n are as defined above.) ECNo.B X R ₄ Z R ₁ R ₂ R ₃ m n3-1 O H H 4-AdaPhO Me H 4-FBz 1 13-2 O H Me 4-AdaPhO Me H 4-FBz 1 03-3 O H Et 4-AdaPhO Me H 4-FBz 1 23-4 O H Pr 4-daPhO Me H 4-FBz 1 33-5 O H iPr 4-AdaPhO Me H 4-FBz 1 43-6 O H Bu 4-AdaPhO Me H 4-FBz 1 53-7 O H iBu 4-AdaPhO Me H 4-FBz 1 63-8 O H sBu 4-AdaPhO Me H 4-FBz 1 73-9 O H tBu 4-AdaPhO Me H 4-FBz 1 83-10 O H Pn 4-AdaPhO Me H 4-FBz 2 13-11 O H iPn 4-AdaPhO Me H 4 -FBz 3 13-12 O H sPn 4-AdaPhO Me H 4-FBz 4 13-13 O H Hx 4-AdaPhO Me H 4-FBz 5 13-14 O H iHx 4-AdaPhO Me H 4-FBz 6 13-15 O H sHx 4-AdaPhO Me H 4-FBz 7 13-16 O H Ph 4-AdaPhO Me H 4-FBz 8 13-17 O H 4-FPh 4-AdaPhO Me H H 1 13-18 O H 4-ClPh 4-AdaPhO Me H Me 1 13-19 O H 3-CF ₃ Ph 4-AdaPhO Me H Et 1 13-20 O H 2-MePh 4-AdaPhO Me H Bu 1 13-21 O H 3-MeOPh 4-AdaPhO Me H Ph 1 13-22 O H 2- FPh 4-AdaPhO Me H Bz 1 13-23 O H Bz 4-AdaPhO Me H 4-ClBz 1 13-24 S H 2-ClBz 4-AdaPhO Me H 4-FBz 1 13-25 O H 4-ClBz 4-AdaPhO Me H 4-FBz 1 13-26 O H 2-FBz 4-AdaPhO 4-FBz H 4-FBz 1 13-27 O H 3-FBz 4-AdaPhO Et H 4-FBz 1 13-28 O H 4-FBz 4-AdaPhO Pr H 4-FBz 1 13-29 O H 2-CF ₃ Bz 4-AdaPhO iPr H 4-FBz 1 13-30 O H 3-CF ₃ Bz 4-AdaPhO Bu H 4-FBz 1 13-31 O H 4-CF ₃ Bz 4 -AdaPhO iBu H 4-FBz 1 13-32 O H 2-MeBz 4-AdaPhO sBu H 4-FBz 1 13-33 O H 3-MeBz 4-AdaPhO Pn H 4-FBz 1 13-34 O H 4-MeBz 4-AdaPhO Hx H 4-FBz 1 13-35 O H 2-MeOBz 4-AdaPhO Ph H 4-FBz 1 13-36 O H 3-MeOBz 4-AdaPhO Bz H 4-FBz 1 13-37 O H 2-BozPh 4-AdaPhO Me Me 4-FBz 1 13-38 O H 2-BozPh 4-AdaPhO Me Et 4-FBz 1 13-39 O H 2-BozPh 4-AdaPhO Me Pr 4-FBz 1 13-40 O H 2-BozPh 4-AdaPhO Me iPr 4- FBz 1 13-41 O H 2-BozPh 4-AdaPhO Me Bu 4-FBz 1 13-42 O H 2-BozPh 4-AdaPhO Me iBu 4-FBz 1 13-43 O H 2-BozPh 4-AdaPhO Me sBu 4-FBz 1 13-44 O H 2-BozPh 4-AdaPhO Me Pn 4-FBz 1 13-45 O H 2-BozPh 4-AdaPhO Me Hx 4-FBz 1 13-46 O H 2-BozPh 4-AdaPhO Me Ph 4-FBz 1 13- 47 O H 2-BozPh 4-AdaPhO Me 4-FPh 4-FBz 1 13-48 O H 2-BozPh 4-AdaPhO Me 3-CF ₃ Ph 4-FBz 1 13-49 O H 2-BozPh 4-AdaPhO Me 3-MeOPh 4-FBz 1 13-50 O H 2-BozPh 4-AdaPhO Me 2-MePh 4-FBz 1 13-51 O H 2-BozPh 4-AdaPhO Me 4-CNPh 4-FBz 1 13-52 O H 2-BozPh 4-AdaPhO Me Bz 4-FBz 1 13-53 O H 2-BozPh 4-AdaPhO Me 3-FBz 4-FBz 1 13-54 O H 2-BozPh 4-AdaPhO Me 2-CF ₃ Bz 4-FBz 1 13-55 O H 2- BozPh 4-AdaPhO Me 3,5-di-MeOBz 4-FBz 1 13-56 O H 2-BozPh 4-AdaPhO Me 4-ClBz 4-FBz 1 13-57 O Cl 2-BozPh 4-AdaPhO Me H 4-FBz 1 13-58 O F 2-BozPh 4-AdaPhO Me H 4-FBz 1 13-59 O Br 2-BozPh 4-AdaPhO Me H 4-FBz 1 13-60 O Me 2-BozPh 4-AdaPhO Me H 4-FBz 1 13-61 O MeO 2-BozPh 4-AdaPhO Me H 4-FBz 1 13-62 O EtO 2-BozPh 4-AdaPhO Me H 4-FBz 1 13-63 O iPr 2-BozPh 4-AdaPhO Me H 4- FBz 1 13-64 O CF ₃ 2-BozPh 4-AdaPhO Me H 4-FBz 1 13-65 O HO 2-BozPh 4-AdaPhO Me H 4-FBz 1 13-66 O EtO 2-BozPh 4-AdaPhO Me H 4-FBz 1 13-67 O tBu 2-BozPh 4-AdaPhO Me H 4-FBz 1 13-68 O Ac 2-BozPh 4-AdaPhO Me H 4-FBz 1 13-69 O Boz 2-BozPh 4-AdaPhO Me H 4-FBz 1 13-70 O PhAc 2-BozPh 4-AdaPhO Me H 4-FBz 1 13-71 O cPnc 2-BozPh 4-AdaPhO Me H 4-FBz 1 13-72 O NH ₂ 2-BozPh 4- AdaPhO Me H 4-FBz 1 13-73 O NHAc 2-BozPh 4-AdaPhO Me H 4-FBz 1 13-74 O NHBoz 2-BozPh 4-AdaPhO Me H 4-FBz 1 13-75 O NHMe H 4-AdaPhO Me H 4-FBz 1 13-76 O NHiPr Me 4-AdaPhO Me H 4-FBz 1 13-77 O NHPh Et 4-AdaPhO Me H 4-FBz 1 13-78 O NHBz Pr 4-AdaPhO Me H 4-FBz 1 13-79 O NMeEt iPr 4-AdaPhO Me H 4-FBz 1 13-80 O NEtPh Bu 4-AdaPhO Me H 4-FBz 1 13-81 O NPhBz iBu 4-AdaPhO Me H 4-FBz 1 13-82 O Ph sBu 4-AdaPhO Me H 4-FBz 1 13-83 O Np tBu 4-AdaPhO Me H 4-FBz 1 13-84 O CN Pn 4-AdaPhO Me H 4-FBz 1 13-85 O NO ₂ iPn 4- AdaPhO Me H 4-FBz 1 13-86 O H Hx 4-HO-3,5-di- Me H 4-FBz 1 1

tBuPhS3-87 O H iHx 4-HO-3,5-Two- Me H H H 1 1

tBuPhS3-88 O H sHx 4-HO-3,5-Two- Me H Me 1 1

tBuPhS3-89 O H Ph 4-HO-3,5-Two- Me H Et 1 1

tBuPhS3-90 O H 4-FPh 4-HO-3,5-Two- Me H H Hx 1 1

tBuPhS3-91 O H 4-ClPh 4-HO-3,5-Two- Me H Bz 1 1

tBuPhS3-92 O H 3-CF ₃ Ph 4-HO-3,5-di-Me H Ph 1 1

tBuPhS3-93 O H 2-MePh 4-HO-3,5-Two- Me H 4-FBz 1 0

tBuPhS3-94 O H 3-MeOPh 4-HO-3,5-Two- Me H 4-FBz 1 2

tBuPhS3-95 O H 2-FPh 4-HO-3,5-Two- Me H 4-FBz 1 3

tBuPhS3-96 O H Bz 4-HO-3,5-Two- Me H 4-FBz 1 4

tBuPhS3-97 O H 3-CIBz 4-HO-3,5-Two- Me H 4-FBz 1 5

tBuPhS3-98 O H 2-ClBz 4-HO-3,5-Two- Me H 4-FBz 1 6

tBuPhS3-99 O H 4-ClBz 4-HO-3,5-Two- Me H 4-FBz 1 7

tBuPhS3-100 O H 2-FBz 4-HO-3,5-Two- Me H 4-FBz 1 8

tBuPhS3-101 O H 3-FBz 4-HO-3,5-Two- Me H 4-FBz 2 1

tBuPhS3-102 O H 4-FBz 4-HO-3,5-Two- Me H 4-FBz 3 1

tBuPhS3-103 O H 2-CF ₃ Bz 4-HO-3,5-di-Me H 4-FBz 4 1

tBuPhS3-104 O H 3-CF ₃ Bz 4-HO-3,5-Di-Me H 4-FBz 5 1

tBuPhS3-105 O H 4-CF ₃ Bz 4-HO-3,5-di-Me H 4-FBz 6 1

tBuPhS3-106 O H 2-MeBz 4-HO-3,5-Two- Me H 4-FBz 7 1

tBuPhS3-107 O H 3-MeBz 4-HO-3,5-Two-Me H 4-FBz 8 1

tBuPhS3-108 S H 2-MeOBz 4-HO-3,5-Two- Me H 4-FBz 1 1

tBuPhS3-109 O H 3-MeOBz 4-HO-3,5-Two- Me H 4-FBz 1 1

BuPhS3-110 O H 4-MeOBz 4-HO-3,5-Two-Me H 4-FBz 1 1

tBuPhO3-111 O H 2-BozPh 4-HO-3,5-Two-Et H 4-FBz 1 1

tBuPhS3-112 O H 2-BozPh 4-HO-3,5-Two- Pr H 4-FBz 1 1

tBuPhS3-113 O H 2-BozPh 4-HO-3,5-Two- iPr H 4-FBz 1 1

tBuPhS3-114 O H 2-BozPh 4-HO-3,5-Two- Bu H 4-FBz 1 1

tBuPhS3-115 O H 2-BozPh 4-HO-3,5-Two- iBu H 4-FBz 1 1

tBuPhS3-116 O H 2-BozPh 4-HO-3,5-Two- sBu H 4-FBz 1 1

tBuPhS3-117 O H 2-BozPh 4-HO-3,5-Two- Pn H 4-FBz 1 1

tBuPhS3-118 O H 2-BozPh 4-HO-3,5-Two- Hx H 4-FBz 1 1

tBuPhS3-119 O H 2-BozPh 4-HO-3,5-Two- Ph H 4-FBz 1 1

tBuPhS3-120 O H 2-BozPh 4-HO-3,5-Two- Bz H 4-FBz 1 1

tBuPhS3-121 O H 2-BozPh 4-HO-3,5-Two- Me Me 4-FBz 1 1

tBuPhS3-122 O H 2-BozPh 4-HO-3,5-Two- Me Et 4-FBz 1 1

tBuPhS3-123 O H 2-BozPh 4-HO-3,5-Two- Me Pr 4-FBz 1 1

tBuPhS3-124 O H 2-BozPh 4-HO-3,5-Two- Me iPr 4-FBz 1 1

tBuPhS3-125 O H 2-BozPh 4-HO-3,5-Two- Me Bu 4-FBz 1 1

tBuPhS3-126 O H 2-BozPh 4-HO-3,5-Two- Me iBu 4-FBz 1 1

tBuPhS3-127 O H 2-BozPh 4-HO-3,5-Two- Me sBu 4-FBz 1 1

tBuPhS3-128 O H 2-BozPh 4-HO-3,5-Two- Me Pn 4-FBz 1 1

tBuPhS3-129 O H 2-BozPh 4-HO-3,5-Two- Me Hx 4-FBz 1 1

tBuPhS3-130 O H 2-BozPh 4-HO-3,5-Two- Me Ph 4-FBz 1 1

tBuPhS3-131 O H 2-BozPh 4-HO-3,5-Two- Me 4-FPh 4-FBz 1 1

tBuPhS3-132 O H 2-BozPh 4-HO-3,5-di-Me 3-CF ₃ Ph 4-FBz 1 1

tBuPhS3-133 O H 2-BozPh 4-HO-3,5-Two- Me 3-MeOPh 4-FBz 1 1

tBuPhS3-134 O H 2-BozPh 4-HO-3,5-Two- Me 2-MePh 4-FBz 1 1

tBuPhS3-135 O H 2-BozPh 4-HO-3,5-Two- Me 4-CNPh 4-FBz 1 1

tBuPhS3-136 O H 2-BozPh 4-HO-3,5-Two- Me Bz 4-FBz 1 1

BuPhS3-137 O H 2-BozPh 4-HO-3,5-Two- Me 3-FBz 4-FBz 1 1

tBuPhS3-138 O H 2-BozPh 4-HO-3,5-di-Me 2-CF ₃ Bz 4-FBz 1 1

tBuPhS3-139 O H 2-BozPh 4-HO-3,5-Two- Me 3,5-TwoMeOBz 4-FBz 1 1

tBuPhS3-140 O H 2-BozPh 4-HO-3,5-Two- Me 4-ClBz 4-FBz 1 1

tBuPhS3-141 O Cl 2-BozPh 4-HO-3,5-Two- Me H 4-FBz 1 1

tBuPhS3-142 O F 2-BozPh 4-HO-3,5-Two- Me H 4-FBz 1 1

tBuPhS3-143 O Br 2-BozPh 4-HO-3,5-Two- Me H 4-FBz 1 1

tBuPhS3-144 O Me 2-BozPh 4-HO-3,5-Two- Me H 4-FBz 1 1

tBuPhS3-145 O MeO 2-BozPh 4-HO-3,5-Two- Me H 4-FBz 1 1

tBuPhS3-146 O EtO 2-BozPh 4-HO-3,5-Two- Me H 4-FBz 1 1

tBuPhS3-147 O iPr 2-BozPh 4-HO-3,5-Two- Me H 4-FBz 1 1

tBuPhS3-148 O CF ₃ H 4-HO-3,5-di-Me H 4-FBz 1 1

tBuPhS3-149 O HO Me 4-HO-3,5-Two- Me H 4-FBz 1 1

tBuPhS3-150 O EtO Et 4-HO-3,5-Two- Me H 4-FBz 1 1

tBuPhS3-151 O tBu Pr 4-HO-3,5-Two- Me H 4-FBz 1 1

tBuPhS3-152 O Ac iPr 4-HO-3,5-Two- Me H 4-FBz 1 1

tBuPhS3-153 O Boz Bu 4-HO-3,5-Two- Me H 4-FBz 1 1

tBuPhS3-154 O PhAc iBu 4-HO-3,5-Two- Me H 4-FBz 1 1

tBuPhS3-155 O cPnc sBu 4-HO-3,5-two- Me H 4-FBz 1 1

tBuPhS3-156 O NH ₂ tBu 4-HO-3,5-di-Me H 4-FBz 1 1

tBuPhS3-157 O NHAc Pn 4-HO-3,5-Two- Me H 4-FBz 1 1

tBuPhS3-158 O NHBoz iPn 4-HO-3,5-Two- Me H 4-FBz 1 1

tBuPhS3-159 O NHMe sPn 4-HO-3,5-Two- Me H 4-FBz 1 1

tBuPhS3-160 O NHiPr Hx 4-HO-3,5-Two- Me H 4-FBz 1 1

tBuPhS3-161 O NHPh iHx 4-HO-3,5-Two- Me H 4-FBz 1 1

tBuPhS3-162 O NHBz sHx 4-HO-3,5-Two- Me H 4-FBz 1 1

tBuPhS3-163 O NMeEt Ph 4-HO-3,5-Two- Me H 4-FBz 1 1

tBuPhS3-164 O NEtPh 4-FPh 4-HO-3,5-Two- Me H 4-FBz 1 1

tBuPhS3-165 O NPhBz 4-CIPh 4-HO-3,5-Two- Me H 4-FBz 1 1

tBuPhS3-166 O Ph 3-CF ₃ Ph 4-HO-3,5-di-Me H 4-FBz 1 1

tBuPhS3-167 O Np 2-MePh 4-HO-3,5-Two- Me H 4-FBz 1 1

tBuPhS3-168 O CN 3-MeOPh 4-HO-3,5-Two- Me H 4-FBz 1 1

tBuPhS3-169 O NO ₂ 2-FPh 4-HO-3,5-di-Me H 4-FBz 1 1

tBuPhS3-170 O H 3-CIBz 4-HO-2,3,5- Me H H H 1 1

Three MePhO3-171 O H 4-ClBz 4-HO-2,3,5- Me H Me 1 1

Three MePhO3-172 O H 2-FBz 4-HO-2,3,5- Me H Et 1 1

Three MePhO3-173 O H 3-FBz 4-HO-2,3,5- Me H Bu 1 1

Three MePhO3-174 O H 4-FBz 4-HO-2,3,5- Me H Ph 1 1

Tri-MePhO3-175 O H 2-CF ₃ Bz 4-HO-2,3,5-Me H Bz 1 1

Three MePhO3-176 O H 3-CF ₃ Bz 4-HO-2,3,5-Me H Bz 1 1

Three MePhO3-177 O H H MeO Me H H 1 13-178 O H 3-MeBz MeO Me H Me 1 13-179 O H 4-MeBz MeO Me H Et 1 13-180 O H 2-MeOBz MeO Me H Pr 1 13-181 O H 3 -MeOBz MeO Me H iPr 1 13-182 O H 4-MeOBz MeO Me H Pn 1 13-183 O H 4-BrBz MeO Me H Hx 1 13-184 O H 2-BozPh MeO Me H Bz 1 13-185 O H 2-BozPh MeO Me H 4-FBz 1 13-186 O H 2-BozPh MeO Me H 3-ClBz 1 13-187 O H 2-BozPh MeO Me H Ph 1 13-188 O H 2-BozPh MeO Me H H 1 13-189 O H 2- BozPh MeO Me H H 1 13-190 O H 2-BozPh MeO Me H H 1 13-191 O H 2-BozPh EtO Me H Bz 1 13-192 O H 2-BozPh PrO Me H Bz 1 13-193 O H 2-BozPh iPrO Me H Bz 1 13-194 O H 2-BozPh BuO Me H Bz 1 13-195 O H 2-BozPh iBuO Me H Bz 1 13-196 O H 2-BozPh sBuO Me H Bz 1 13-197 O H 2-BozPh tBuO Me H Bz 1 13-198 O H 2-BozPh PnO Me H Bz 1 13-199 O H 2-BozPh HxO Me H Bz 1 13-200 O H 2-BozPh PhO Me H Bz 1 13-201 O H 2-BozPh 4-ClPhO Me H Bz 1 13-202 O H 2-BozPh 4-FPhO Me H Bz 1 13-203 O H 2-BozPh 2-FPhO Me H Bz 1 13-204 O H 2-BozPh 3-FPhO Me H Bz 1 13-205 O H 2-BozPh 4 -CF ₃ PhO Me H Bz 1 13-206 O H 2-BozPh 3-CF ₃ PhO Me H Bz 1 13-207 O H 2-BozPh 4-MeOPhO Me H Bz 1 13-208 O H 2-BozPh 4-MePhO Me H Bz 1 13-209 O H 2-BozPh 4-PhPhO Me H Bz 1 13-210 O H 2-BozPh 3-HOPhO Me H Bz 1 13-211 O H 2-BozPh 3-AcPhO Me H Bz 1 13-212 O H 2- BozPh 4-cPrPhO Me H Bz 1 13-213 O H 2-BozPh 4-Me ₂ NPhO Me H Bz 1 13-214 O H 2-BozPh 4-CNPhO Me H Bz 1 13-215 O H 2-BozPh 4-NO ₂ PhO Me H Bz 1 13-216 O H 2-BozPh Me Me H Bz 1 13-217 O H 2-BozPh Et Me H Bz 1 13-218 O H 2-BozPh tBu Me H Bz 1 13-219 O H 2-BozPh Hx Me H Bz 1 13-220 O H 2-BozPh Ph Me H Bz 1 13-221 O H 2-BozPh Np Me H Bz 1 13-222 O H 2-BozPh 4-MeOPh Me H Bz 1 13-223 O H 2-BozPh Bz Me H Bz 1 13-224 O H 2-BozPh 4-CF ₃ Bz Me H Bz 1 13-225 O H 2-BozPh MeS Me H Bz 1 13-226 O H 2-BozPh PhS Me H Bz 1 13-227 O H 2-BozPh BzS Me H Bz 1 13-228 O H H 4-FPhS Me H Bz 1 13-229 O H Me 4-CF ₃ PhS Me H Bz 1 13-230 O H Et 4-FBzS Me H Bz 1 13-231 O H Pr F Me H Bz 1 13-232 O H iPr Cl Me H Bz 1 13-233 O H Bu Br Me H Bz 1 13-234 O H iBu 2-PyrS Me H Bz 1 13-235 O H sBu 3-PyrS Me H 4-FBz 1 13-236 O H tBu 4-PyrS Me H 4-CF ₃ Bz 1 13-237 O H Pn 2-PyrO Me H 3-MeOBz 1 13-238 O H iPn 3-PyrO Me H Bz 1 13-239 O H sPn 4-PyrO Me H Bz 1 13-240 O H Hx cPrS Me H Bz 1 13-241 O H iHx cHxS Me H Bz 1 13-242 O H sHx NH ₂ Me H Bz 1 13-243 O H Ph NHMe Me H Bz 1 13-244 O H 4-FPh NMeEt Me H Bz 1 13-245 O H 4-ClPh NHAc Me H Bz 1 13-246 O H 3-CF ₃ Ph NHPh Me H Bz 1 13-247 O H 2-MePh NHBz Me H Bz 1 13-248 O H 3-MeOPh NHBoz Me H Bz 1 13-249 O H 2-FPh NMeBoz Me H Bz 1 13-250 O H Bz NEtBz Me H Bz 1 13-251 O H 3-CIBz NPhBz Me H Bz 1 13-252 O H 2-CIBz NPhBoz Me H Bz 1 13-253 O H 4-ClBz NH(4-FBoz) Me H Bz 1 13-254 O H 2-FBz NH(3-Me H Bz 1 1

MeOBoz)3-255 O H 3-FBz NHBoz Me Me Bz 1 13-256 O H 4-FBz NHBoz Me Et Bz 1 13-257 O H 2-CF ₃ Bz NHBoz Me Ph Bz 1 13-258 O H 3-CF ₃ Bz NHBoz Me Bz Bz 1 13-259 O H H 4-AdaPhO Me H MeSO ₂ 1 13-260 O H H 4-HO-3,5-di-Me H MeSO ₂ 1 1

tBuPhS3-261 O H H MeO Me H MeSO ₂ 1 13-262 O H H 4-AdaPhO Me H Tos 1 13-263 O H H 4-HO-3,5-Di-Me H Tos 1 1

tBuPhS3-264 O H H MeO Me H Tos 1 13-265 O H H 4-AdaPhO Me H CF ₃ SO ₂ 1 13-266 O H H 4-HO-3,5-Di-Me H CF ₃ SO ₂ 1 1

tBuPhS3-267 O H H MeO Me H CF ₃ SO ₂ 1 13-268 O H H 4-AdaPhO Me H Bz 1 13-269 O H H 4-HO-3,5-Di-Me H Bz 1 1

tBuPhS3-270 O H H MeO Me H Bz 1 13-271 O H H 4-AdaPhO Me H CF ₃ SO ₂ 1 13-272 O H H 4-HO-3,5-Di-Me H CF ₃ SO ₂ 1 1

tBuPhS3-273 O H H MeO Me H CF ₃ SO ₂ 1 13-274 O H 4-CF ₃ Bz 4-H ₂ N-3,5-di-Me H H 1 1

MePhO3-275 O H 3-MeBz 4-H ₂ N-3,5-di-Me H Me 1 1

MePhO3-276 O H 4-MeBz 4-H ₂ N-3,5-Di-MeH Et 1 1

MePhO3-277 O H 2-MeOBz 4-H ₂ N-3,5-di-Me H Pr 1 1

MePhO3-278 O H 3-MeOBz 4-H ₂ N-3,5-Di-MeH iPr 1 1

MePhO3-279 O H 4-MeOBz 4-H ₂ N-3,5-di-Me H Pn 1 1

MePhO3-280 O H 4-BrBz 4-H ₂ N-3,5-di-MeH Hx 1 1

MePhO3-281 O H 2-BozPh 4-H ₂ N-3,5-di-Me H Bz 1 1

MePhO3-282 O H 2-BozPh 4-H ₂ N-3,5-di-Me H 4-FBz 1 1

MePhO3-283 O H 2-BozPh 4-H ₂ N-3,5-di-Me H 3-ClBz 1 1

MePhO3-284 O H 2-BozPh 4-H ₂ N-3,5-di-MeH Ph 1 1

MePhO3-285 O H 2-BozPh 4-H ₂ N-3,5-Di-MeHH 1 1

MePhO3-286 O H 3-BozPh 4-H ₂ N-3,5-Di-MeHH 1 1

MePhO3-287 O H 4-BozPh 4-H ₂ N-3,5-Di-MeHH 1 1

MePhO3-288 O H 4-CF ₃ Bz 4-(4- Me H H 1 1

CF ₃ PhCarNH)-

                                                                   

CF ₃ PhCarNH)-

                                                       

CF ₃ PhCarNH)-

                                                        , 

CF ₃ PhCarNH)-

                                                                                  

CF ₃ PhCarNH)-

                                                                      

CF ₃ PhCarNH)-

                                                              

CF ₃ PhCarNH)-

                                                                                                   

CF ₃ PhCarNH)-

                                                               

CF ₃ PhCarNH)-

                                                                     

CF ₃ PhCarNH)-

                                                                                

CF ₃ PhCarNH)-

                                                                                  

CF ₃ PhCarNH)-

                                                                                           

CF ₃ PhCarNH)-

                                                                             

CF ₃ PhCarNH)-

                                                            

(式中R₁、R₂、R₃、R₄、A、B、W₁、W₂、X、Y、Z₄、m和n同上定义。)E.C.No. B  X    R₄       Z           R₁ R₂   R₃    m    n4-1     O  H    3-ClBz    4-AdaPhO    Me  H    4-FBz    1    14-2     O  H    3-ClBz    4-AdaPhO    Me  H    4-FBz    1    04-3     O  H    3-ClBz    4-AdaPhO    Me  H    4-FBz    1    24-4     O  H    3-ClBz    4-AdaPhO    Me  H    4-FBz    1    34-5     O  H    3-ClBz    4-AdaPhO    Me  H    4-FBz    1    44-6     O  H    3-ClBz    4-AdaPhO    Me  H    4-FBz    1    54-7     O  H    3-ClBz    4-AdaPhO    Me  H    4-FBz    1    64-8     O  H    3-ClBz    4-AdaPhO    Me  H    4-FBz    1    74-9     O  H    3-ClBz    4-AdaPhO    Me  H    4-FBz    1    84-10    O  H    3-ClBz    4-AdaPhO    Me  H    4-FBz    2    14-11    O  H    3-ClBz    4-AdaPhO    Me  H    4-FBz    3    14-12    O  H    3-ClBz    4-AdaPhO    Me  H    4-FBz    4    14-13    O  H        3-ClBz    4-AdaPhO    Me  H    4-FBz    5  14-14    O  H        3-ClBz    4-AdaPhO    Me  H    4-FBz    6  14-15    O  H        3-ClBz    4-AdaPhO    Me  H    4-FBz    7  14-16    O  H        3-ClBz    4-AdaPhO    Me  H    4-FBz    8  14-17    O  NPhBz    sPn       4-AdaPhO    Me  H    4-FBz    1  14-18    O  NPhBz    sPn       4-AdaPhO    Me  H    4-FBz    1  04-19    O  NPhBz    sPn       4-AdaPhO    Me  H    4-FBz    1  24-20    O  NPhBz    sPn       4-AdaPhO    Me  H    4-FBz    1  34-21    O  NPhBz    sPn       4-AdaPhO    Me  H    4-FBz    1  44-22    O  NPhBz    sPn       4-AdaPhO    Me  H    4-FBz    1  54-23    O  NPhBz    sPn       4-AdaPhO    Me  H    4-FBz    1  64-24    O  NPhBz    sPn       4-AdaPhO    Me  H    4-FBz    1  74-25    O  NPhBz    sPn       4-AdaPhO    Me  H    4-FBz    1  84 26    O  NPhBz    sPn       4-AdaPhO    Me  H    4-FBz    2  14-27    O  NPhBz    sPn       4-AdaPhO    Me  H    4-FBz    3  14-28    O  NPhBz    sPn       4-AdaPhO    Me  H    4-FBz    4  14-29    O  NPhBz    sPn       4-AdaPhO    Me  H    4-FBz    5  14-30    O  NPhBz    sPn       4-AdaPhO    Me  H    4-FBz    6  14-31    O  NPhBz    sPn       4-AdaPhO    Me  H    4-FBz    7  14-32    O  NPhBz    sPn       4-AdaPhO    Me  H    4-FBz    8  14-33    O  H        4-MeBz    4-HO-3，5-二-tBuPhS    Me  H    4-FBz    1    14-34    O  H        4-MeBz    4-HO-3，5-二-tBuPhS    Me  H    4-FBz    1    04-35    O  H        4-MeBz    4-HO-3，5-二-tBuPhS    Me  H    4-FBz    1    24-36    O  H        4-MeBz    4-HO-3，5-二-tBuPhS    Me  H    4-FBz    1    34-37    O  H        4-MeBz    4-HO-3，5-二-tBuPhS    Me  H    4-FBz    1    44-38    O  H        4-MeBz    4-HO-3，5-二-tBuPhS    Me  H    4-FBz    1    54-39    O  H        4-MeBz    4-HO-3，5-二-tBuPhS    Me  H    4-FBz    1    64-40    O  H        4-MeBz    4-HO-3，5-二-tBuPhS    Me  H    4-FBz    1    74-41    O  H        4-MeBz    4-HO-3，5-二-tBuPhS    Me  H    4-FBz    1    84-42    O  H        4-MeBz    4-HO-3，5-二-tBuPhS    Me  H    4-FBz    2    14-43    O  H        4-MeBz    4-HO-3，5-二-tBuPhS    Me  H    4-FBz    3    14-44    O  H        4-MeBz    4-HO-3，5-二-tBuPhS    Me  H    4-FBz    4    14-45    O  H        4-MeBz    4-HO-3，5-二-tBuPhS    Me  H    4-FBz    5    14-46    O  H        4-MeBz    4-HO-3，5-二-tBuPhS    Me  H    4-FBz    6    14-47    O  H        4-MeBz    4-HO-3，5-二-tBuPhS    Me  H    4-FBz    7    14-48    O  H        4-MeBz    4-HO-3，5-二-tBuPhS    Me  H    4-FBz    8    14-49    O  NPhBz    Bz        4-HO-3，5-二-tBuPhS    Me  H    4-FBz    1    14-50    O  NPhBz    Bz        4-HO-3，5-二-tBuPhS    Me  H    4-FBz    1    04-51    O  NPhBz    Bz        4-HO-3，5-二-tBuPhS    Me  H    4-FBz    1    24-52    O  NPhBz    Bz        4-HO-3，5-二-tBuPhS    Me  H    4-FBz    1    34-53    O  NPhBz    Bz    4-HO-3，5-二-tBuPhS    Me    H    4-FBz    1    44-54    O  NPhBz    Bz    4-HO-3，5-二-tBuPhS    Me    H    4-FBz    1    54-55    O  NPhBz    Bz    4-HO-3，5-二-tBuPhS    Me    H    4-FBz    1    64-56    O  NPhBz    Bz    4-HO-3，5-二-tBuPhS    Me    H    4-FBz    1    74-57    O  NPhBz    Bz    4-HO-3，5-二-tBuPhS    Me    H    4-FBz    1    84-58    O  NPhBz    Bz    4-HO-3，5-二-tBuPhS    Me    H    4-FBz    2    14-59    O  NPhBz    Bz    4-HO-3，5-二-tBuPhS    Me    H    4-FBz    3    14-60    O  NPhBz    Bz    4-HO-3，5-二-tBuPhS    Me    H    4-FBz    4    14-61    O  NPhBz    Bz    4-HO-3，5-二-tBuPhS    Me    H    4-FBz    5    14-62    O  NPhBz    Bz    4-HO-3，5-二-tBuPhS    Me    H    4-FBz    6    14-63    O  NPhBz    Bz    4-HO-3，5-二-tBuPhS    Me    H    4-FBz    7    14-64    O  NPhBz    Bz    4-HO-3，5-二-tBuPhS    Me    H    4-FBz    8    1[Table 4]

(where R ₁ , R ₂ , R ₃ , R ₄ , A, B, W ₁ , W ₂ , X, Y, Z ₄ , m and n are as defined above.) ECNo. B X R ₄ Z R ₁ R ₂ R ₃ m n4-1 O H 3-ClBz 4-AdaPhO Me H 4-FBz 1 14-2 O H 3-ClBz 4-AdaPhO Me H 4-FBz 1 04-3 O H 3-ClBz 4-AdaPhO Me H 4-FBz 1 24- 4 O H 3-ClBz 4-AdaPhO Me H 4-FBz 1 34-5 O H 3-ClBz 4-AdaPhO Me H 4-FBz 1 44-6 O H 3-ClBz 4-AdaPhO Me H 4-FBz 1 54-7 O H 3-ClBz 4-AdaPhO Me H 4-FBz 1 64-8 O H 3-ClBz 4-AdaPhO Me H 4-FBz 1 74-9 O H 3-ClBz 4-AdaPhO Me H 4-FBz 1 84-10 O H 3- ClBz 4-AdaPhO Me H 4-FBz 2 14-11 O H 3-ClBz 4-AdaPhO Me H 4-FBz 3 14-12 O H 3-ClBz 4-AdaPhO Me H 4-FBz 4 14-13 O H 3-ClBz 4 -AdaPhO Me H 4-FBz 5 14-14 O H 3-ClBz 4-AdaPhO Me H 4-FBz 6 14-15 O H 3-ClBz 4-AdaPhO Me H 4-FBz 7 14-16 O H 3-ClBz 4-AdaPhO Me H 4-FBz 8 14-17 O NPhBz sPn 4-AdaPhO Me H 4-FBz 1 14-18 O NPhBz sPn 4-AdaPhO Me H 4-FBz 1 04-19 O NPhBz sPn 4-AdaPhO Me H 4-FBz 1 24-20 O NPhBz sPn 4-AdaPhO Me H 4-FBz 1 34-21 O NPhBz sPn 4-AdaPhO Me H 4-FBz 1 44-22 O NPhBz sPn 4-AdaPhO Me H 4-FBz 1 54-23 O NPhBz sPn 4-AdaPhO Me H 4-FBz 1 64-24 O NPhBz sPn 4-AdaPhO Me H 4-FBz 1 74-25 O NPhBz sPn 4-AdaPhO Me H 4-FBz 1 84 26 O NPhBz sPn 4-AdaPhO Me H 4-FBz 2 14-27 O NPhBz sPn 4-AdaPhO Me H 4-FBz 3 14-28 O NPhBz sPn 4-AdaPhO Me H 4-FBz 4 14-29 O NPhBz sPn 4-AdaPhO Me H 4-FBz 5 14-30 O NPhBz sPn 4-AdaPhO Me H 4-FBz 6 14-31 O NPhBz sPn 4-AdaPhO Me H 4-FBz 7 14-32 O NPhBz sPn 4-AdaPhO Me H 4-FBz 8 14-33 O H 4 -MeBz 4-HO-3,5-di-tBuPhS Me H 4-FBz 1 14-34 O H 4-MeBz 4-HO-3,5-di-tBuPhS Me H 4-FBz 1 04-35 O H 4-MeBz 4-HO-3,5-di-tBuPhS Me H 4-FBz 1 24-36 O H 4-MeBz 4-HO-3,5-di-tBuPhS Me H 4-FBz 1 34-37 O H 4-MeBz 4- HO-3,5-di-tBuPhS Me H 4-FBz 1 44-38 O H 4-MeBz 4-HO-3,5-di-tBuPhS Me H 4-FBz 1 54-39 O H 4-MeBz 4-HO- 3,5-Di-tBuPhS Me H 4-FBz 1 64-40 O H 4-MeBz 4-HO-3,5-Di-tBuPhS Me H 4-FBz 1 74-41 O H 4-MeBz 4-HO-3, 5-Di-tBuPhS Me H 4-FBz 1 84-42 O H 4-MeBz 4-HO-3,5-Di-tBuPhS Me H 4-FBz 2 14-43 O H 4-MeBz 4-HO-3,5- Di-tBuPhS Me H 4-FBz 3 14-44 O H 4-MeBz 4-HO-3,5-Di-tBuPhS Me H 4-FBz 4 14-45 O H 4-MeBz 4-HO-3,5-Di- tBuPhS Me H 4-FBz 5 14-46 O H 4-MeBz 4-HO-3,5-Di-tBuPhS Me H 4-FBz 6 14-47 O H 4-MeBz 4-HO-3,5-Di-tBuPhS Me H 4-FBz 7 14-48 O H 4-MeBz 4-HO-3,5-di-tBuPhS Me H 4-FBz 8 14-49 O NPhBz Bz 4-HO-3,5-di-tBuPhS Me H 4- FBz 1 14-50 O NPhBz Bz 4-HO-3,5-di-tBuPhS Me H 4-FBz 1 04-51 O NPhBz Bz 4-HO-3,5-di-tBuPhS Me H 4-FBz 1 24- 52 O NPhBz Bz 4-HO-3,5-di-tBuPhS Me H 4-FBz 1 34-53 O NPhBz Bz 4-HO-3,5-di-tBuPhS Me H 4-FBz 1 44-54 O NPhBz Bz 4-HO-3,5-di-tBuPhS Me H 4-FBz 1 54-55 O NPhBz Bz 4-HO-3,5-di-tBuPhS Me H 4-FBz 1 64-56 O NPhBz Bz 4-HO- 3,5-di-tBuPhS Me H 4-FBz 1 74-57 O NPhBz Bz 4-HO-3,5-di-tBuPhS Me H 4-FBz 1 84-58 O NPhBz Bz 4-HO-3,5- Di-tBuPhS Me H 4-FBz 2 14-59 O NPhBz Bz 4-HO-3,5-Di-tBuPhS Me H 4-FBz 3 14-60 O NPhBz Bz 4-HO-3,5-Di-tBuPhS Me H 4-FBz 4 14-61 O NPhBz Bz 4-HO-3,5-di-tBuPhS Me H 4-FBz 5 14-62 O NPhBz Bz 4-HO-3,5-di-tBuPhS Me H 4-FBz 6 14-63 O NPhBz Bz 4-HO-3,5-di-tBuPhS Me H 4-FBz 7 14-64 O NPhBz Bz 4-HO-3,5-di-tBuPhS Me H 4-FBz 8 1

(式中R₁、R₂、R₃、A、B、W₁、W₂、X、Y、Z₁、m和n同上定义。)E.C.No. B  X    Y    Z      R₁ R₂  R₃  m    n5-1     O  H    S    MeO    Me  H    H     1    15-2     O  H    SO   MeO    Me  H    H     1    15-3     O  H    SO₂ MeO    Me  H    H     1    15-4     O  H    S    MeO    Me  H    Me    1    15-5     O  H    S    MeO    Me  H    Me    1    05-6     O  H    S    MeO    Me  H    Me    1    25-7     O  H    S    MeO    Me  H    Me    1    35-8     O  H    S    MeO    Me  H    Me    1    45-9     O  H    S    MeO    Me  H    Me    1    55-10    O  H    S    MeO    Me  H    Me    1    65-11    O  H    S    MeO    Me  H    Me    1    75-12    O  H    S    MeO    Me  H    Me    1    85-13    O  H    S    MeO   Me  H    Me  2    15-14    O  H    S    MeO   Me  H    Me  3    15-15    O  H    S    MeO   Me  H    Me  4    15-16    O  H    S    MeO   Me  H    Me  5    15-17    O  H    S    MeO   Me  H    Me  6    15-18    O  H    S    MeO   Me  H    Me  7    15-19    O  H    S    MeO   Me  H    Me  8    15-20    O  H    S    MeO   Me  H    Me  2    25-21    O  H    SO   MeO   Me  H    Me  1    15-22    O  H    SO₂ MeO   Me  H    Me  1    15-23    O  H    S    HO    Me  H    H   1    15-24    O  H    SO   HO    Me  H    H   1    15-25    O  H    SO₂ HO    Me  H    H   1    15-26    O  H    S    HO    Me  H    Me  1    15-27    O  H    S    HO    Me  H    Me  1    05-28    O  H    S    HO    Me  H    Me  1    25-29    O  H    S    HO    Me  H    Me  1    35-30    O  H    S    HO    Me  H    Me  1    45-31    O  H    S    HO    Me  H    Me  1    55-32    O  H    S    HO    Me  H    Me  1    65-33    O  H    S    HO    Me  H    Me  1    75-34    O  H    S    HO    Me  H    Me  1    85-35    O  H    S    HO    Me  H    Me  2    15-36    O  H    S    HO    Me  H    Me  3    15-37    O  H    S    HO    Me  H    Me  4    15-38    O  H    S    HO    Me  H    Me  5    15-39    O  H    S    HO    Me  H    Me  6    15-40    O  H    S    HO    Me  H    Me  7    15-41    O  H    S    HO    Me  H    Me  8    15-42    O  H    S    HO    Me  H    Me  2    25-43    O  H    SO   HO    Me  H    Me  1    15-44    O  H    SO₂ HO    Me  H    Me  1    15-45    O  H    S    GlcA  Me  H    H   1    15-46    O  H    SO   GlcA  Me  H    H   1    15-47    O  H    SO₂ GlcA  Me  H    H   1    15-48    O  H    S    GlcA  Me  H    Me  1    15-49    O  H    S    GlcA  Me  H    Me  1    05-50    O  H    S    GlcA  Me  H    Me  1    25-51    O  H    S    GlcA  Me  H    Me  1    35-52    O  H    S    GlcA    Me  H    Me  1    45-53    O  H    S    GlcA    Me  H    Me  1    55-54    O  H    S    GlcA    Me  H    Me  1    65-55    O  H    S    GlcA    Me  H    Me  1    75-56    O  H    S    GlcA    Me  H    Me  1    85-57    O  H    S    GlcA    Me  H    Me  2    15-58    O  H    S    GlcA    Me  H    Me  3    15-59    O  H    S    GlcA    Me  H    Me  4    15-60    O  H    S    GlcA    Me  H    Me  5    15-61    O  H    S    GlcA    Me  H    Me  6    15-62    O  H    S    GlcA    Me  H    Me  7    15-63    O  H    S    GlcA    Me  H    Me  8    15-64    O  H    S    GlcA    Me  H    Me  2    25-65    O  H    SO   GlcA    Me  H    Me  1    15-66    O  H    SO₂ GlcA    Me  H    Me  1    15-67    O  H    S    MeS     Me  H    Me  1    15-68    O  H    S    MeS     Me  H    H   1    1[table 5]

(R ₁ , R ₂ , R ₃ , A, B, W ₁ , W ₂ , X, Y, Z ₁ , m and n are as defined above.) ECNo. B X Y Z R ₁ R ₂ R ₃ m n5-1 O H S MeO Me H H 1 15-2 O H SO MeO Me H H 1 15-3 O H SO ₂ MeO Me H H 1 15-4 O H S MeO Me H Me 1 15-5 O H S MeO Me H Me 1 05-6 O H S MeO Me H Me 1 25 -7 O H S MeO Me H Me 1 35-8 O H S MeO Me H Me 1 45-9 O H S MeO Me H Me 1 55-10 O H S MeO Me H Me 1 65-11 O H S MeO Me H Me 1 75-12 O H S MeO Me H Me 1 85-13 O H S MeO Me H Me 2 15-14 O H S MeO Me H Me 3 15-15 O H S MeO Me H Me 4 15-16 O H S MeO Me H Me 5 15-17 O H S MeO Me H Me 6 15- 18 O H S MeO Me H Me 7 15-19 O H S MeO Me H Me 8 15-20 O H S MeO Me H Me 2 25-21 O H SO MeO Me H Me 1 15-22 O H SO ₂ MeO Me H Me 1 15-23 O H S HO Me H H 1 15-24 O H SO HO Me H H 1 15-25 O H SO ₂ HO Me H H 1 15-26 O H S HO Me H Me 1 15-27 O H S HO Me H Me 1 05-28 O H S HO Me H Me 1 25-29 O H S HO Me H Me 1 35-30 O H S HO Me H Me 1 45-31 O H S HO Me H Me 1 55-32 O H S HO Me H Me 1 65-33 O H S HO Me H Me 1 75-34 O H S HO Me H Me 1 85-35 O H S HO Me H Me 2 15-36 O H S HO Me H Me 3 15-37 O H S HO Me H Me 4 15-38 O H S HO Me H Me 5 15-39 O H S HO Me H Me 6 15 -40 O H S HO Me H Me 7 15-41 O H S HO Me H Me 8 15-42 O H S HO Me H Me 2 25-43 O H SO HO Me H Me 1 15-44 O H SO ₂ HO Me H Me 1 15-45 O H S GlcA Me H H 1 15-46 O H SO GlcA Me H H 1 15-47 O H SO ₂ GlcA Me H H 1 15-48 O H S GlcA Me H Me 1 15-49 O H S GlcA Me H Me 1 05-50 O H S GlcA Me H Me 1 25-51 O H S GlcA Me H Me 1 35-52 O H S GlcA Me H Me 1 45-53 O H S GlcA Me H Me 1 55-54 O H S GlcA Me H Me 1 65-55 O H S GlcA Me H Me 1 75-56 O H S GlcA Me H Me 1 85-57 O H S GlcA Me H Me 2 15-58 O H S GlcA Me H Me 3 15-59 O H S GlcA Me H Me 4 15-60 O H S GlcA Me H Me 5 15-61 O H S GlcA Me H Me 6 15-62 O H S GlcA Me H Me 7 15-63 O H S GlcA Me H Me 8 15-64 O H S GlcA Me H Me 2 25-65 O H SO GlcA Me H Me 1 15-66 O H SO ₂ GlcA Me H Me 1 15- 67 O H S MeS Me H Me 1 15-68 O H S MeS Me H H 1 1

In the above table,

The following exemplified compound numbers are preferred:

1-1 3-[4-[6-(4-adamantane-1-ylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2-( 4-fluorobenzyloxy)propanoic acid,

1-86 3-[4-[6-(3,5-di-tert-butyl-4-hydroxyphenylthio)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl] -2-(4-fluorobenzyloxy)propanoic acid,

1-87 4-[6-(3,5-di-tert-butyl-4-hydroxyphenylthio)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyllactic acid,

1-170 4-[6-(4-Hydroxy-2,3,5-trimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyllactic acid,

1-177 4-(1-Methyl-6-methoxy-1H-benzimidazol-2-ylmethoxy)phenyllactic acid,

1-179 2-ethoxy-3-[4-(1-methyl-6-methoxy-1H-benzimidazol-2-ylmethoxy)phenyl]propanoic acid,

3-188 N-(2-benzoylphenyl)-4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenylalanine,

3-285 4-[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]-N-(2-benzene formylphenyl)phenylalanine,

3-299 4-[6-[4-(4-trifluoromethylphenylureido)-3,5-di-methylphenoxy]-1-methyl-1 H-benzimidazole-2 -ylmethoxy]-N-(2-benzoylphenyl)phenylalanine,

5-1 3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-mercaptopropionic acid,

5-4 3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionic acid,

5-21 3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylsulfinylpropionic acid,

5-22 3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylsulfonylpropionic acid,

5-23 3-[4-(6-Hydroxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-mercaptopropionic acid,

5-26 3-[4-(6-Hydroxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionic acid,

5-43 3-[4-(6-Hydroxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylsulfinylpropionic acid,

5-45 3-[4-[6-(β-D-glucopyranosyloxyuronic acid)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]- 2-mercaptopropionic acid,

5-48 3-[4-[6-(β-D-glucopyranosyloxyuronic acid)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]- 2-methylthiopropionic acid,

5-65 3-[4-[6-(β-D-glucopyranosyloxyuronic acid)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]- 2-Methylsulfinylpropionic acid,

5-67 3-[4-(1-methyl-6-methylthio-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionic acid,

5-68 3-[4-(1-methyl-6-methylthio-1H-benzimidazol-2-ylmethoxy)phenyl]-2-mercaptopropionic acid,

Its pharmaceutically acceptable esters or its pharmaceutically acceptable amides or its pharmaceutically acceptable salts.

More preferably:

1-1 3-[4-[6-(4-adamantane-1-ylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2-( 4-fluorobenzyloxy)propanoic acid,

1-86 3-[4-[6-(3,5-di-tert-butyl-4-hydroxyphenylthio)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl] -2-(4-fluorobenzyloxy)propanoic acid,

1-87 4-[6-(3,5-di-tert-butyl-4-hydroxyphenylthio)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyllactic acid,

1-170 4-[6-(4-Hydroxy-2,3,5-trimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyllactic acid,

1-177 4-(1-Methyl-6-methoxy-1H-benzimidazol-2-ylmethoxy)phenyllactic acid,

1-179 2-ethoxy-3-[4-(1-methyl-6-methoxy-1H-benzimidazol-2-ylmethoxy)phenyl]propanoic acid,

3-188 N-(2-benzoylphenyl)-4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenylalanine,

3-285 4-[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]-N-(2-benzene formylphenyl)phenylalanine,

3-299 4-[6-[4-(4-trifluoromethylphenylureido)-3,5-dimethylphenoxy]-1-methyl-1H-benzimidazol-2-yl Methoxy]-N-(2-benzoylphenyl)phenylalanine,

5-1 3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-mercaptopropionic acid,

5-4 3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionic acid,

5-21 3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylsulfinylpropionic acid,

5-22 3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylsulfonylpropionic acid,

5-26 3-[4-(6-Hydroxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionic acid,

5-48 3-[4-[6-(β-D-glucopyranosyloxyuronic acid)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]- 2-methylthiopropionic acid,

5-67 3-[4-(1-methyl-6-methylthio-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionic acid,

5-68 3-[4-(1-methyl-6-methylthio-1H-benzimidazol-2-ylmethoxy)phenyl]-2-mercaptopropionic acid,

Its pharmaceutically acceptable esters or its pharmaceutically acceptable amides or its pharmaceutically acceptable salts.

Most preferred are:

1-1 3-[4-[6-(4-adamantane-1-ylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2-( 4-fluorobenzyloxy)propanoic acid,

1-86 3-[4-[6-(3,5-di-tert-butyl-4-hydroxyphenylthio)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl] -2-(4-fluorobenzyloxy)propanoic acid,

1-179 2-ethoxy-3-[4-(1-methyl-6-methoxy-1H-benzimidazol-2-ylmethoxy)phenyl]propanoic acid,

3-188 N-(2-benzoylphenyl)-4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenylalanine,

3-285 4-[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]-N-(2-benzene formylphenyl)phenylalanine,

5-21 3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylsulfinylpropionic acid,

5-67 3-[4-(1-methyl-6-methylthio-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionic acid,

Its pharmaceutically acceptable esters or its pharmaceutically acceptable amides or its pharmaceutically acceptable salts.

The compounds of general formula (I) of the present invention can be prepared by the following methods.

Method A:

In the formula, R ₁ , R ₂ , R ₃ , W ₁ , W ₂ , X, Y, A and B have the same meanings as above, and Z represents the above-mentioned Z ₁ , Z ₂ O-group, Z ₃ S-group or Z ₄ , Y' represents the above-mentioned Y or NR ₄ group (R ₄ represents the same meaning as above), and R represents the above-mentioned ester residue.

Method A is a process for preparing compounds of general formula (I)-(IV), which is carried out in an inert solvent by reacting a compound of general formula (V) with water in the presence of an acid or a base .

The inert solvent used in the above reaction is not particularly limited as long as it is a substance inactive in the present reaction, for example, aliphatic hydrocarbons such as hexane, heptane, volatile oil, petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene ; Halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, di (ethylene glycol) dimethyl ether; amides such as dimethylformamide, dimethylacetamide, hexamethylphosphoryl triamide; alcohols such as methanol, ethanol, propanol; water and mixed solvents of the above solvents. Preferable are ethers, alcohols, amides, water, and mixed solvents of the above solvents (more preferably alcohols and ethers, particularly preferably toluene and tetrahydrofuran).

The acid used in the above reaction is not particularly limited as long as it is a substance used as an acid catalyst in a usual reaction, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, phosphoric acid; Bronsted Acids, including organic acids such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, etc.; Lewis acids such as zinc chloride, tetrachloride Tin, boron trichloride, boron trifluoride, boron tribromide; acidic ion exchange resins. Preference is given to inorganic acids and organic acids (especially preferably hydrochloric acid, acetic acid and trifluoroacetic acid).

As long as the base used in the above reaction has no effect on other parts of the compound, there is no particular limitation, for example, alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate; alkali metal bicarbonates such as lithium bicarbonate, carbonic acid Sodium hydrogen, potassium bicarbonate; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide; ammonia such as ammonia water, concentrated ammonia - Methanol. Preference is given to alkali metal hydroxides and metal alkoxides (particularly alkali metal hydroxides and metal alkoxides).

The reaction temperature varies depending on the starting compound, solvent, etc., and is usually -20°C to 150°C (preferably 0°C to 60°C).

The reaction time varies with raw material compounds, solvents, and reaction temperature, and is usually 30 minutes to 5 days (preferably 5 hours to 72 hours).

When R is a benzyl group that can be substituted, the process can make the compound (V) undergo a catalytic reduction reaction in an inert solvent to prepare the target compound (I)-( IV).

The catalyst used in the above-mentioned catalytic reduction reaction is not particularly limited as long as it is a catalyst used in a common catalytic reduction reaction, such as palladium-on-carbon, Raney nickel, rhodium-coated alumina, triphenylphosphine-rhodium oxide , Palladium-barium sulfate, palladium black, platinum oxide, platinum black, preferably palladium carbon.

The inert solvent used in the above-mentioned catalytic reduction reaction is not particularly limited as long as it is inactive in the reaction, such as aliphatic hydrocarbons such as hexane, heptane, volatile oil, petroleum ether; aromatic hydrocarbons such as benzene, toluene or xylene; Halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethyl Glycol dimethyl ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, Cyclohexanol, methyl cellosolve; amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoryl triamide; organic acids such as acetic acid, trifluoroacetic acid; and mixed solvents of the above solvents. Preference is given to ethers, alcohols and organic acids (particularly alcohols).

The reaction temperature varies depending on the starting compound, the catalyst used, the solvent, etc., and is usually 0°C-100°C (preferably 10°C-50°C).

The reaction time varies with the raw material compound, the catalyst used, the solvent, and the reaction temperature, and is usually 30 minutes to 48 hours. Method B

In the formula, R ₁ , R ₂ , R ₃ , W ₁ , W ₂ , X, Y', Z, A, B and R represent the same meanings as above, and the Boc group represents tert-butoxycarbonyl.

Method B is a process for preparing a compound of general formula (V) by reacting a compound of general formula (VI) with a compound of general formula (VII), followed by acid treatment. That is, in this method, there is no isolation and purification process of the amide compound as an intermediate, and the tert-butoxycarbonyl group protecting the amino group is removed with an acid to form a ring in the same manner as the above reaction.

Alternatively, this method can also be carried out by contacting with an acid (B2 step) after separating and purifying the intermediate (VIII) obtained by reacting compound (VI) and compound (VII) (B1 step).

Step B1 is carried out as follows.

(a) Acid halide method

The acid halide method is to make compound (VII) and a halogenating agent (such as thionyl chloride, thionyl bromide, oxalic acid chlorine (shuyu acid clolid; oxalic chloride), oxalic acid dichloride (shuyu acid jiclolid; oxalic dichloride) in an inert solvent , phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, etc.) react to obtain an acid halide, and in an inert solvent, the resulting acid halide is reacted with compound (VI) or its The acid addition salt reaction is carried out.

Examples of the base used in the above reaction are: alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate; alkali metal bicarbonates such as lithium bicarbonate, sodium bicarbonate, potassium bicarbonate; alkali metal hydrides such as hydrogen Lithium, sodium hydride, potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkali metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide; organic amines such as triethyl Amine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, N,N-di Ethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo [5.4.0]-7-Undecene (DBU). Preference is given to organic amines (particularly triethylamine).

The inert solvent used in the above reaction is not particularly limited as long as it is an inert solvent in the reaction, for example, aliphatic hydrocarbons such as hexane, heptane, volatile oil, petroleum ether; aromatic hydrocarbons such as benzene, toluene, xylene; halogenated Hydrocarbons such as dichloromethane, chloroform, 1,2-dichloroethane, carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol Dimethyl ether; ketones such as acetone; amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoryl triamide; sulfoxides such as dimethyl sulfoxide; and sulfolane. Preference is given to halogenated hydrocarbons, ethers and amides (particularly dichloromethane, chloroform, tetrahydrofuran and dimethylformamide).

The reaction temperature varies with the raw material compounds, reagents, etc., the reaction between the halogenating agent and the compound (VII) and the reaction between the acid halide and the compound (VI) or its acid addition salt is usually at -20°C-150°C, preferably the halogenating agent and The reaction of compound (VII) is at -10°C to 100°C, and the reaction of acid halide with compound (VI) or its acid addition salt is at -20°C to 100°C.

The reaction time is different with raw material compound, reagent, reaction temperature etc., and the reaction of halogenating agent and compound (VII) and the reaction of acyl halide and compound (VI) or its acid addition salt are generally all in 30 minutes-80 hours (preferably 1 hour-48 hours).

(b) Active ester method

The active ester method is in an inert solvent, after compound (VII) is reacted with an active esterifying agent to obtain an active ester, in the presence or absence of (preferably present) a base, in an inert solvent, it is combined with the compound ( VI) or its acid addition salt reaction.

Preferred active esterifying agents used in the above reaction are N-hydroxy compounds such as N-hydroxysuccinimide, 1-hydroxybenzotriazole, N-hydroxy-5-norbornene-2,3-dicarboxy imide; disulfide such as dipyridyl disulfide; carbodiimide such as dicyclohexylcarbodiimide; carbonyldiimidazole; triphenylphosphine and other condensing agents.

The inert solvent used in the above reaction is not particularly limited as long as it is an inert substance in the reaction, for example, aliphatic hydrocarbons such as hexane, heptane, volatile oil, petroleum ether; aromatic hydrocarbons such as benzene, toluene, xylene; halogenated Hydrocarbons such as dichloromethane, 1,2-dichloroethane, carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl Base ethers; ketones such as acetone; amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoryl triamide; sulfoxides such as dimethyl sulfoxide; sulfolane. Preference is given to ethers and amides (particular preference is given to dioxane, tetrahydrofuran and dimethylformamide).

Examples of the base used in the above reaction include the same bases used in the above acid halide method.

The reaction temperature varies with raw material compounds, reagents, etc., usually the temperature of the active esterification reaction is -70°C-150°C (preferably -10°C-100°C), active esters and compound (VI) or its acid addition salt The reaction temperature is -20°C-100°C (preferably 0°C-50°C).

The reaction time varies with raw material compounds, reagents, reaction temperature, etc., and the reaction of active esterification and active esters with compound (VI) or its acid addition salt is usually 30 minutes-80 hours (preferably 1 hour-48 hours) ).

(c) mixed anhydride method

The mixed acid anhydride method is in an inert solvent, in the presence or absence of (preferably existing) under the condition of alkali, after compound (VII) is reacted with the mixed anhydride agent to obtain the mixed anhydride, in the inert solvent, the mixed anhydride and the compound ( VI) or its acid addition salt reaction.

Examples of the base used in the above reaction are alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate; alkali metal bicarbonates such as lithium bicarbonate, sodium bicarbonate, potassium bicarbonate; alkali metal hydrides such as lithium hydride , sodium hydride, potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkali metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide; organic amines such as triethylamine , tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, N,N-diethyl Aniline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diazabicyclo[ 5.4.0] -7-Undecene (DBU). Preference is given to organic amines (particularly triethylamine).

Examples of mixed anhydrides used in the above reaction include C ₁ -C ₄ alkyl carbonate halides such as ethyl chloroformate, isobutyl chloroformate; C ₁ -C ₅ alkanoyl halides such as pivaloyl chloride; Di-C ₁ -C ₄ alkyl or di-C ₆ -C ₁₄ aryl cyanophosphoric acid such as diethyl cyanophosphonate, diphenyl cyanophosphonate. Preference is given to di-C ₁ -C ₄ -alkyl or di-C ₆ -C ₁₄ aryl cyanophosphoric acids (particularly diethyl cyanophosphonate).

The inert solvent used in the preparation of mixed anhydrides is not particularly limited as long as it does not hinder the reaction and can dissolve the starting material to a certain extent, such as aliphatic hydrocarbons such as hexane, heptane, volatile oil, petroleum ether; aromatic hydrocarbons such as benzene , toluene, xylene; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane alkanes, diethylene glycol dimethyl ether; ketones such as acetone; amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoryl triamide; sulfoxides such as dimethyl sulfoxide; Sulfolane. Ethers and amides are preferred (tetrahydrofuran and dimethylformamide are particularly preferred).

The reaction temperature of the reaction for preparing the mixed acid anhydride varies with raw material compounds, reagents, etc., and is usually -50°C to 100°C (preferably 0°C to 60°C).

The reaction time of the reaction for preparing the mixed acid anhydride varies with raw material compounds, reagents, reaction temperature, etc., and is usually 30 minutes to 72 hours (preferably 1 hour to 24 hours).

The reaction of the mixed acid anhydride with the compound (VI) or its acid addition salt is carried out in an inert solvent in the presence or absence of (preferably) a base, and the base used and the inert solvent are the same as those mentioned above in the preparation of the mixed anhydride. The base and inert solvent used in the reaction are the same.

The reaction temperature of the reaction of the mixed acid anhydride with the compound (VI) or its acid addition salt varies with the raw material compounds, reagents, etc., and is usually -30°C-100°C (preferably 0°C-80°C).

The reaction time of the reaction between the mixed acid anhydride and compound (VI) or its acid addition salt varies with the raw material compounds, reagents, reaction temperature, etc., and is usually 5 minutes to 24 hours (preferably 30 minutes to 16 hours).

In addition, in this reaction, when using di-C ₁ -C ₄ alkyl cyanophosphoric acid or di-C ₆ -C ₁₄ aryl cyano phosphoric acid, compound (VI) and compound ( VII) Direct Response.

After the reaction is completed, the target compound (VIII) of the reaction is extracted from the reaction mixture according to a conventional method. For example, the reaction mixture is properly neutralized, and in the case of insoluble matter exists, the insoluble matter is removed by filtration, water and an immiscible organic solvent such as ethyl acetate are added, the organic layer containing the target compound is separated, and washed with water, etc. Then, after drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate, etc., the solvent was distilled off to obtain the target compound.

Step B2, that is, the ring-closing reaction with an acid is carried out by reacting the compound (VIII) in an inert solvent in the presence of an acid.

The acid to be used is not particularly limited as long as it is used as an acid catalyst in a normal reaction. Examples include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, phosphoric acid; Bronsted acids, including, for example, acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid, Organic acids such as trifluoromethanesulfonic acid, etc.; Lewis acids such as zinc chloride, tin tetrachloride, boron trichloride, boron trifluoride, boron tribromide; acidic ion exchange resins. Preference is given to inorganic acids and organic acids (especially preferably hydrochloric acid, acetic acid and trifluoroacetic acid).

The inert solvent used in the above reaction is not particularly limited as long as it is inactive in the reaction. For example, aliphatic hydrocarbons such as hexane, heptane, volatile oil, petroleum ether; aromatic hydrocarbons such as benzene, toluene, xylene; halogenated hydrocarbons such as chloroform, methylene chloride, 1,2-dichloroethane, carbon tetrachloride; esters Such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol Dimethyl ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerol, octanol, cyclohexane Alcohol, methyl cellosolve; amides such as formamide, dimethylformamide, dimethylacetamide hexamethylphosphoryl triamide; water; or a mixed solvent of water and the above solvents. Preference is given to ethers and amides (particular preference is given to dioxane, tetrahydrofuran and dimethylformamide).

The reaction temperature varies depending on the starting compound, the acid used, the solvent, etc., and is usually -20°C to boiling point temperature (preferably 0°C-100°C).

The reaction time varies depending on the starting compound, the acid used, the solvent, the reaction temperature, etc., and is usually 15 minutes to 48 hours (preferably 30 minutes to 20 hours).

Step B3 is the process of functional group transformation of the -YR ₃ base of the general formula (VIII), which is for the general formula (VIII': the -YR ₃ base in the compound represented by the general formula (VIII) is the substance of the -OH group) The represented compound is subjected to (i) Mitsunobu reaction, (ii) etherification reaction, (iii) alkanesulfonylation (or arylsulfonylation), followed by thioetherification or (iv) alkanesulfonylation ( Or aryl sulfonylation), azidation reaction and reduction reaction, synthesize -YR in the compound represented by general formula (VIII ": general formula (VIII) ₃ base is the material of alkoxy group, alkylthio group or amino ) represented by the compound.

In this process,

(i) Mitsunobu reaction is a step for preparing a compound of the general formula (VIII'), which is carried out in an inert solvent between phosphine (preferably tributylphosphine and triphenylphosphine) and azodicarboxylic acid compound (preferably in the presence of diethyl azodicarboxylate and 1,1-dipiperidine azodicarboxylate).

(ii) The etherification reaction can be carried out in the same manner as in the following D1 step.

(iii) The step of carrying out the thioetherification reaction after the alkanesulfonylation (or arylsulfonylation) can be carried out in the same manner as the following F1 step.

(iv) The steps of carrying out azidation reaction and reduction reaction after alkanesulfonylation (or arylsulfonylation) can be carried out in the same manner as the following G1 step. The amino compound can also be alkylated with an alkyl halide according to the following H1 step, and an alkyl amide can be obtained through ordinary reductive alkylation with an aldehyde or a ketone. Method C

In the above formula, R ₂ , R ₃ , W ₁ , W ₂ , X, Y', B and R represent the same meanings as above.

Method C is a method for preparing a compound of general formula (VII) by reacting a compound of general formula (IX) in an inert solvent in the presence of an acid.

The acid used is not particularly limited as long as it can be used as an acid catalyst in a normal reaction. Examples include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, phosphoric acid; Bronsted acids, including, for example, acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid, Organic acids such as trifluoromethanesulfonic acid, etc.; Lewis acids such as zinc chloride, tin tetrachloride, boron trichloride, boron trifluoride, boron tribromide; acidic ion exchange resins. Preference is given to inorganic acids and organic acids (especially preferably hydrochloric acid, acetic acid and trifluoroacetic acid).

The inert solvent used in the above reaction is not particularly limited as long as it is inactive in the reaction. For example, aliphatic hydrocarbons such as hexane, heptane, volatile oil, petroleum ether; aromatic hydrocarbons such as benzene, toluene, xylene; halogenated hydrocarbons such as chloroform, methylene chloride, 1,2-dichloroethane, carbon tetrachloride; esters Such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol Dimethyl ether; alcohols such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol, isoamyl alcohol, diethylene glycol, glycerol, octanol, cyclohexane Alcohol, methyl cellosolve; amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoryl triamide; water; or a mixed solvent of water and the above solvents. Preference is given to ethers and amides (particular preference is given to dioxane, tetrahydrofuran and dimethylformamide).

The reaction temperature varies depending on the starting compound, the acid used, the solvent, etc., and is usually -20°C to boiling point temperature (preferably 0°C-80°C).

The reaction time varies depending on the starting compound, the acid used, the solvent, the reaction temperature, etc., and is usually 15 minutes to 48 hours (preferably 30 minutes to 20 hours).

Method D

In the above formula, R ₂ , R ₃ , W ₁ , W ₂ , X, Y', B and R represent the same meanings as above, and the Halo group represents the above-mentioned halogen atom.

Method D is a method for preparing a compound of general formula (IX), which is to make a compound of general formula (X) and a compound represented by general formula R ₃ -Halo in an inert solvent in the presence of a base or silver oxide halide reaction.

Examples of the base used in the above reaction are: alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate; alkali metal bicarbonates such as lithium bicarbonate, sodium bicarbonate, potassium bicarbonate; alkali metal hydrogenation Such as lithium hydride, sodium hydride, potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkali metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide; organic amines Such as triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-bis Azabicyclo[5.4.0]-7-undecene (DBU). Preference is given to alkali metal hydrides (particularly sodium hydride).

The inert solvent used in the above reaction is not particularly limited as long as it is inactive in the reaction. For example, aliphatic hydrocarbons such as hexane, heptane, volatile oil, petroleum ether; aromatic hydrocarbons such as benzene, toluene, xylene; halogenated hydrocarbons such as chloroform, methylene chloride, 1,2-dichloroethane, carbon tetrachloride; esters Such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol Dimethyl ether; amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoryl triamide; or a mixed solvent of the above solvents. Preference is given to ethers and amides (particular preference is given to dioxane, tetrahydrofuran and dimethylformamide).

The reaction temperature varies depending on the starting compound, the acid used, the solvent, etc., and is usually -20°C to boiling point temperature (preferably 0°C-100°C).

The reaction time varies depending on the starting compound, the base used, the solvent, the reaction temperature, etc., and is usually 15 minutes to 48 hours (preferably 30 minutes to 20 hours).

Method E

In the above formula, R ₂ , W ₁ , W ₂ , X, B, R and Halo group have the same meanings as above.

Method E is a process for preparing a compound of general formula (XIII), which is to react a compound of general formula (XI) with a halogenated compound represented by general formula (XII) in the presence of a base or silver oxide in an inert solvent. reacted by substances.

Examples of the base used in the above reaction are alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate; alkali metal bicarbonates such as lithium bicarbonate, sodium bicarbonate, potassium bicarbonate; alkali metal hydrides Such as lithium hydride, sodium hydride, potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkali metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide; organic amines such as Triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, N,N -Diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diaza Heterobicyclo[5.4.0]-7-undecene (DBU). Preference is given to alkali metal hydrides and alkali metal carbonates (particularly sodium hydride, potassium carbonate, cesium carbonate).

The inert solvent used in the above reaction is not particularly limited as long as it is inactive in the reaction, for example, aliphatic hydrocarbons such as hexane, heptane, volatile oil, petroleum ether; aromatic hydrocarbons such as benzene, toluene, xylene; halogenated Hydrocarbons such as chloroform, methylene chloride, 1,2-dichloroethane, carbon tetrachloride; Esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate; Ketones such as acetone , butanone; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; amides such as formamide, dimethylformamide, dimethylformamide Acetamide, hexamethylphosphoryl triamide; or a mixed solvent of the above solvents. Preference is given to ketones, ethers and amides (particular preference is given to acetone, dioxane, tetrahydrofuran and dimethylformamide).

The reaction temperature varies depending on the starting compound, the acid used, the solvent, etc., and is usually -20°C to boiling point temperature (preferably 0°C-100°C).

The reaction time varies depending on the starting compound, the acid used, the solvent, the reaction temperature, etc., and is usually 15 minutes to 48 hours (preferably 30 minutes to 20 hours). Method F

In the above formula, R ₂ , R ₃ , W ₁ , W ₂ , X, B and R represent the same meanings as above.

Method F is a process for preparing a compound of general formula (XIV) by reacting a compound of general formula (XIII) with methanesulfonyl chloride in the presence of a base in an inert solvent, then in the presence of a base, It is carried out by reacting with a thiol represented by the general formula R ₃ SH.

Examples of bases used in step F1 of the above reaction are alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate; alkali metal bicarbonates such as lithium bicarbonate, sodium bicarbonate, potassium bicarbonate; alkali metal hydrides Such as lithium hydride, sodium hydride, potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkali metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide; organic amines such as Triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, N,N -Diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diaza Heterobicyclo[5.4.0]-7-undecene (DBU). Preference is given to organic amines (particularly triethylamine). The base used in the second stage of the above reaction is the same as that used in the first stage, preferably an alkali metal hydride (particularly sodium hydride).

The inert solvent used in the above reaction is not particularly limited as long as it is inactive in the reaction, for example, aliphatic hydrocarbons such as hexane, heptane, volatile oil, petroleum ether; aromatic hydrocarbons such as benzene, toluene, xylene; halogenated Hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, carbon tetrachloride; esters such as methyl acetate, ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate; ethers such as di Diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoryl Triamine; or a mixed solvent of the above solvents. Preference is given to ethers and amides (particular preference is given to dioxane, tetrahydrofuran and dimethylformamide).

The reaction temperature varies depending on the starting compound, the acid used, the solvent, etc., and is usually -20°C to boiling point temperature (preferably 0°C-100°C).

The reaction time varies depending on the starting compound, the acid used, the solvent, the reaction temperature, etc., and is usually 15 minutes to 48 hours (preferably 30 minutes to 20 hours).

Method G

In the above formula, R ₂ , R ₃ , W ₁ , W ₂ , X, Y, B and R represent the same meanings as above.

Method G is a process for preparing a compound of general formula (XV) by reacting a compound of general formula (XIII) with methanesulfonyl chloride in the presence of a base in an inert solvent, and then reacting with sodium azide Reaction occurs to form azides, which are then reduced.

After the reaction with methanesulfonyl chloride, the reaction conditions with sodium azide are the same as for step F1 above (except that no base is required for the second stage). A further reduction reaction is carried out according to the method for converting an azide compound to an amino group (catalytic reduction reaction and reaction with a phosphine described above). Method H

In the above formula, R ₂ , R ₃ , R ₄ , W ₁ , W ₂ , X, B and R represent the same meanings as above.

Process H is a process for the preparation of compounds of general formula (XVI) by alkylating, aralkylating or arylation the amino groups of compounds of general formula (XV).

In this process, the alkylation or aralkylation of the amino group can be carried out according to the known synthetic method of reacting the amino group with an alkyl halide or aralkyl halide, and the arylation of the amino group can be carried out in the presence of a base, The known synthesis of reacting an amino group with an aryl halide is carried out.

Examples of bases used in the H1 step of the above reaction are alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate; alkali metal bicarbonates such as lithium bicarbonate, sodium bicarbonate, potassium bicarbonate; alkali metal hydrides Such as lithium hydride, sodium hydride, potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; alkali metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide; organic amines such as Triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, N,N-dimethylaniline, N,N -Diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,8-diaza Heterobicyclo[5.4.0]-7-undecene (DBU). Alkali metal bicarbonates are preferred. Method I

In the above formula, R ₂ , R ₃ , R ₄ , W ₁ , W ₂ , X, B and R represent the same meanings as above.

Method I is the process of preparing a compound of general formula (XVI), which is to carry out the same alkylation, aralkylation or arylation as method H to the amino group of the compound of general formula (XVII) (I1 step ) After that, the same reaction (I2 step) as in the E1 step is further carried out. In this process, the amino group can also be reacted after being protected by a commonly used protecting group.

Method J

In the above formula, R ₂ , W ₂ , X, B and R represent the same meanings as above.

Method J is a process for preparing a compound of general formula (XX), which can be obtained by converting a ketone or aldehyde of general formula (XIX) into a cyanohydrin, followed by hydrolysis or alcoholysis in the presence of an acid.

The process can be carried out with zinc iodide as catalyst in the presence or absence of an inert solvent.

Also, the compound represented by the general formula (XVII) can be produced by the Streckel synthesis, which is a general synthetic method of amino acids, by reacting hydrogen cyanide and ammonia on a ketone or aldehyde of the general formula (XIX). Method K

In the above formula, R ₁ , Z, A and Boc group have the same meanings as above.

Method K is a process for preparing a compound of general formula (VI), which is to react a compound of general formula (XXI) with a compound of general formula Z-H in an inert solvent in the presence of a base (K1 step ), then carry out the reduction reaction (K2 step) to carry out.

The base used in step K1 is the same as that used in step D1 above, preferably an alkali metal hydride (particularly sodium hydride). The reaction conditions were also carried out according to step D1 above.

K2 step is the reduction reaction of aromatic nitro group, according to the commonly used catalytic reduction reaction, the reduction reaction carried out by the combination of metal and acid (zinc-acetic acid, tin-alcohol or tin-hydrochloric acid) or the reaction with sodium dithionite conduct. Method L

In the above formula, R ₁ , A and Boc group have the same meanings as above.

Method L is a process for preparing a compound of general formula (XXI), which is to introduce an amino-protecting group tert-butyl on a compound of general formula (XXIII) in the presence or absence of a base in an inert solvent Oxycarbonyl (L1 step), followed by alkylation, arylation or aralkylation (L2 step).

Step L1 is a reaction step in which (XXIII) is reacted with di-tert-butyl dicarbonate in the presence of a base in an inert solvent to introduce an amino protecting group (Bocylation).

The L2 step is carried out by alkylation, arylation or aralkylation of the amino group protected by the Boc group according to conventional methods.

Moreover, when there is an amino group on Z in the above-mentioned general formula (I)-(IV) and intermediate (VI), it can be carried out by alkylation, arylation, aralkylation or conventional methods of the above-mentioned amino group Acylation, sulfonylation, carbamoylation. Method M

In the above formula, R ₁ , R ₂ , W ₁ , W ₂ , X, Z, A, B, R, Boc group and Halo group represent the same meanings as above.

Method M is another synthetic method of the compound whose -YR ₃ group is a hydroxyl group in the general formula (I)-(III).

M1 step is to add acetonide to the hydroxyl group and carboxyl group of the compound with general formula (XXV), the process of preparing general formula (XXVI), this process is under the condition of presence or absence (preferably non-existence) inert solvent, in It is carried out by reacting a compound of general formula (XXV) with acetone or 2,2-dimethoxypropane in the presence of an acid.

The acid used is not particularly limited as long as it is used as an acid catalyst in a usual reaction, and its examples include: inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, phosphoric acid; Bronsted acid , including organic acids such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, etc.; Lewis acids such as zinc chloride, tin tetrachloride , boron trichloride, boron trifluoride, boron tribromide; acidic ion exchange resin. Preference is given to inorganic acids and organic acids (especially preferably hydrochloric acid, acetic acid and trifluoroacetic acid).

The reaction temperature varies depending on the raw material compound and the acid used, and is usually -20°C to boiling point (preferably 0°C-80°C).

The reaction time varies depending on the starting compound, the acid used, the reaction temperature, etc., and is usually 15 minutes to 48 hours (preferably 30 minutes to 20 hours).

The M2 step is the process of preparing a compound of general formula (XXVII), which is carried out in an inert solvent by reacting a compound of general formula (XXVI) with a compound of general formula (XII) in the presence of a base of. The reaction can be carried out according to Method E.

Step M3 is a process for preparing the compound of general formula (XXVIII), which is carried out by reacting the compound of general formula (XXVII) in an inert solvent in the presence of an acid. The reaction can be carried out according to Method C.

The M4 step is a process for preparing a compound of general formula (XXIX), which is to react a compound of general formula (XXVIII) with a compound of general formula (VI) in an inert solvent in the presence of a condensing agent. ongoing. This reaction can be carried out according to Method B1.

M5 step is the process of preparing the compound with general formula (XXX) or (XXXI), and this process is under the presence of acid, makes the compound with general formula (XXIX) in inert solvent and water or alcohol (water or alcohol also can be used as a solvent) to react. The reaction can be carried out according to step B2.

The compound in which Y is an S(O)p group (wherein p represents an integer of 0-2) can be synthesized as follows. Method N

In the above formula, R ₁ , R ₃ , W ₁ , W ₂ , X, Z, A, B and R represent the same meanings as above.

Method N is a method for preparing compounds of general formula (XXXV), (XXXVI), (XXXVII), (XXXVIII), (XXXIX) and (XL).

Step N1 is a process for preparing a compound of general formula (XXXIII), which is carried out by reacting a compound of general formula (VI) with a compound of general formula (XXXII) according to the above-mentioned step B1.

N2 step is the process of preparing the compound of general formula (XXXIV), which is carried out by reacting the compound of general formula (XXXIII) according to the above B2 step.

Step N3 is a process for preparing a compound of general formula (XXXV), which is carried out by reacting a compound of general formula (XXXIV) according to the above-mentioned step A1. Step N3 is carried out by reacting a compound of general formula (XXXIV) with water in the presence of a base in an inert solvent.

The inert solvent used in the above reaction is not particularly limited as long as it is not active in the reaction, and its examples are: aliphatic hydrocarbons such as hexane, heptane, volatile oil, sherwood oil; aromatic hydrocarbons such as benzene, toluene, xylene; Halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethyl Glycol dimethyl ether; amides such as dimethylformamide, dimethylacetamide, hexamethylphosphoryl triamide; alcohols such as methanol, ethanol, propanol; water; and mixed solvents of the above solvents. Preferred are ethers, alcohols, amides, water, and mixed solvents of the above solvents, (more preferably alcohols and ethers, particularly preferably ethanol and tetrahydrofuran).

The base used in the above reaction is not particularly limited as long as it has no effect on other parts of the compound, and its examples are: alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate; alkali metal bicarbonates such as bicarbonate Lithium, sodium bicarbonate, potassium bicarbonate; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide; ammonia such as ammonia water , Concentrated ammonia-methanol. Preference is given to alkali metal hydroxides and metal alkoxides (particularly alkali metal hydroxides and metal alkoxides).

The reaction temperature varies depending on the starting compound, solvent, etc., but is usually -20°C to 150°C (preferably 0°C to 100°C).

The reaction time varies depending on the raw material compound, solvent, reaction temperature, etc., and is usually 30 minutes to 5 days (preferably 2 hours to 72 hours).

N4 step is the process of preparing the compound with the general formula (XXXVI), which is carried out by esterifying the compound with the general formula (XXXV). According to the above-mentioned B1 step, the alcohol represented by the general formula ROH is used to replace the compound with the general formula ROH The compound of the general formula (IV) is reacted by (a) acid halide method, (b) active ester method or (c) mixed acid anhydride method.

It can also be carried out by reacting a compound having the general formula (XXXV) and an alcohol represented by the general formula ROH in the presence of an acid in an inert solvent or using the alcohol as a solvent. The inert solvent used in the above reaction is not particularly limited as long as it is not active in the reaction, and its examples are: aliphatic hydrocarbons such as hexane, heptane, volatile oil, sherwood oil; aromatic hydrocarbons such as benzene, toluene, xylene; Halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethyl Glycol dimethyl ether; amides such as dimethylformamide, dimethylacetamide, hexamethylphosphoryl triamide; alcohols such as methanol, ethanol, propanol; water; and mixed solvents of the above solvents. Preferable are ethers, alcohols, amides, and mixed solvents of the above solvents (more preferably alcohols and ethers, particularly preferably alcohols and tetrahydrofuran).

The acid used in the above reaction is not particularly limited as long as it is used as an acid catalyst in a common reaction, and its examples are: inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, phosphoric acid; Stead's acid, including organic acids such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, etc.; Lewis acids such as zinc chloride, Tin tetrachloride, boron trichloride, boron trifluoride, boron tribromide; acidic ion exchange resins. Preference is given to inorganic acids and organic acids (especially preferably hydrochloric acid, acetic acid and trifluoroacetic acid).

The reaction temperature varies depending on the starting compound, solvent, etc., and is usually -20°C to 150°C (preferably 0°C to 60°C).

The reaction time varies depending on the raw material compound, solvent, reaction temperature, etc., and is usually 30 minutes to 5 days (preferably 5 hours to 72 hours).

N5 step is the process of preparing a compound with general formula (XXXVII), which is to make a compound with general formula (XXXVI) and a compound with general formula R ₃ -Halo (R ₃ is not a hydrogen atom) according to the above-mentioned D1 step reaction to proceed.

N6 step is the process of preparing the compound with the general formula (XXXVIII), which is carried out by subjecting the compound with the general formula (XXXVII) to the hydrolysis reaction of the ester according to the above-mentioned A1 step.

Step N7 is a process for preparing the compound of general formula (XXXIX), which is carried out by reacting the compound of general formula (XXXVIII) with ammonia according to the above-mentioned step B1.

Step N8 is a process for preparing a compound of general formula (XL) by reacting a compound of general formula (XXXV) with ammonia according to the above-mentioned step B1.

N9 step is the process of preparing a compound with general formula (XXXIX), which is to make a compound with general formula (XL) and a compound with general formula R ₃ -Halo (R ₃ is not a hydrogen atom) according to the above-mentioned D1 step reaction to proceed. Method O

In the above formula, R ₁ , R ₃ , W ₁ , W ₂ , X, Z, A, B and R represent the same meanings as above.

Method O is the preparation of compounds of general formula (XLI), (XLII), (XLIII), (XLIV), (XLV) and (XLVI) by oxidation of sulfides.

The O1 step is the process of preparing compounds of general formula (XLI) and (XLII) by reacting a compound of general formula (XXXVII) with a peroxide such as m-chloroperbenzene in the presence or absence of a base. Formic acid, hydrogen peroxide or tert-butyl hydroperoxide react in an inert solvent. The inert solvent used in the above reaction is not particularly limited as long as it is not active in the reaction, and its examples are: aliphatic hydrocarbons such as hexane, heptane, volatile oil, sherwood oil; aromatic hydrocarbons such as benzene, toluene, xylene; Halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethyl Glycol dimethyl ether; amides such as dimethylformamide, dimethylacetamide, hexamethylphosphoryl triamide; alcohols such as methanol, ethanol, propanol; water; and mixed solvents of the above solvents. Preferred are halogenated hydrocarbons, alcohols, amides, and mixed solvents of the above solvents (more preferably alcohols and halogenated hydrocarbons, particularly preferably alcohols and dichloromethane).

The base used in the above reaction is not particularly limited as long as it has no effect on other parts of the compound, and its examples are: alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate; alkali metal bicarbonates such as bicarbonate Lithium, sodium bicarbonate, potassium bicarbonate; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide; ammonia such as ammonia water , Concentrated ammonia-methanol. Preference is given to alkali metal carbonates or alkali metal hydrogencarbonates (particularly alkali metal hydrogencarbonates).

The reaction temperature varies depending on the starting compound, solvent, etc., and is usually -20°C to 150°C (preferably 0°C to 60°C).

The reaction time varies depending on the starting compound, solvent, reaction temperature, etc., and is usually 1 minute to 1 day (preferably 5 minutes to 2 hours).

O2 step is the process of preparing compounds with general formula (XLIII) and (XLIV). Same as O1 step, this process is to make the compound with general formula (XXXVIII) according to the above-mentioned O1 step in the presence or absence of a base. It is carried out by reacting with peroxides such as m-chloroperbenzoic acid, hydrogen peroxide or tert-butyl hydroperoxide in an inert solvent.

O3 step is the process of preparing compounds with general formula (XLV) and (XLVI), the same as O1 step, this process is to make the compound with general formula (XXXIX) in the presence or absence of base according to the above O1 step It is carried out by reacting with peroxides such as m-chloroperbenzoic acid, hydrogen peroxide or tert-butyl hydroperoxide in an inert solvent. Method P

In the above formula, R ₁ , R ₃ , W ₁ , W ₂ , X, Z, A, B and R represent the same meaning as above, Z' represents the benzyloxy group in the definition of Z, and Z" represents the benzyloxy group in the definition of Z The saturated heterooxyl group (can have 1-5 substituting part α ₁ ), wherein the substituting part α ₁ is a protected group, and Z_ represents the saturated heterooxyl group in the definition of Z (can have 1-5 substituting moieties α ₁ ).

Method P is to prepare the compound (I) of the present invention in which Z is a saturated heterocyclic epoxy group (which may have 1-5 substituent moieties α ₁ ), that is, to prepare compounds with general formulas (LI), (LII), (LIII) , (LIV), (LV) and (LVI) compounds.

Step P1 is a process for preparing a compound of general formula (XLVII) by reacting a compound of general formula (XXII', wherein Z' represents benzyloxy) in an inert solvent according to the above-mentioned K2 step.

Step P2 is the process of preparing a compound of general formula (XLVIII), which is carried out by reacting a compound of general formula (XLVII) with a compound of general formula (XXXII) in an inert solvent according to the above-mentioned step B1.

Step P3 is the process of preparing the compound of general formula (XLIX), which is carried out by reacting the compound of general formula (XLVIII) in an inert solvent according to the above-mentioned step B2.

P4 step is the process of preparing the compound with general formula (L), which process is according to J.Am.Chem.Soc., 77, 3310 (1955) or Chem.Pharm.Bull.39 (8), 2124-2125 ( 1991), make the compound with general formula (XLIX) and the compound such as 1,2,3,4-tetra-O-acetyl-β-D-glucopyranose corresponding to its substituting part be protected Z group Methyl uronic acid methyl ester (1,2,3,4-tetra-O-acetyl-β-D-piranuronic acid Mechel; Methyl1,2,3,4-tetra-O-acetyl-β-D-glucopyranuronate), etc. The reaction takes place in an inert solvent.

P5 step is the process of preparing the compound with general formula (LI), which process is according to J.Am.Chem.Soc., 77, 3310 (1955) or Chem.Pharm.Bull.39 (8), 2124-2125 ( 1991), by hydrolyzing the compound of general formula (L) in an inert solvent.

Step P6 is the process of preparing the compound of general formula (LII), which is carried out by hydrolyzing the compound of general formula (L) in an inert solvent according to the above-mentioned step A1.

Step P7 is the process of preparing the compound of general formula (LII), which is carried out by hydrolyzing the compound of general formula (LI) in an inert solvent according to the above step A1.

Step P8 is a process for preparing the compound of general formula (LIII), which is carried out by reacting the compound of general formula (LII) with ammonia in an inert solvent according to the above-mentioned step B1.

P9 step is the process of preparing the compound with general formula (LIV), this process is to make the compound with general formula (LIII) and the compound with general formula R ₃ -Halo (R ₃ is not a hydrogen atom) in the process according to the above-mentioned D1 step The reaction takes place in an inert solvent.

Step P10 is a process for preparing a compound of general formula (LV), which is carried out by esterifying a compound of general formula (LII) and reacting it according to the above-mentioned N4 step.

The P11 step is the process of preparing a compound with the general formula (LVI), which is to make the compound with the general formula (LV) and the compound with the general formula R ₃ -Halo (R ₃ is not a hydrogen atom) according to the above-mentioned D1 step. The reaction takes place in an inert solvent. Method Q

In the above formula, R ₁ , R ₃ , W ₁ , W ₂ , X, Z_, A, B and R represent the same meanings as above, except that R ₃ is not a hydrogen atom.

Method Q is to prepare compounds with general formulas (LVII) and (LVIII) first, and then, like method O, prepare by carrying out sulfide oxidation reaction on compounds with general formulas (LVII), (LVIII) and (LVI) Process for compounds of general formula (LIX), (LX), (LXI), (LXII), (LXIII) and (LXIV).

Step Q1 is the process of preparing the compound with general formula (LVII), which is carried out by hydrolyzing the compound with general formula (LVI) in an inert solvent according to the above step A1.

Step Q2 is a process for preparing the compound of general formula (LVIII), which is carried out by reacting the compound of general formula (LVII) with ammonia in an inert solvent according to the above-mentioned step B1.

Step Q3 is the process of preparing compounds of general formula (LIX) and (LX), which process is to make the compound of general formula (LVI) and peroxide according to the above O1 step in the presence or absence of a base. For example, m-chloroperbenzoic acid, hydrogen peroxide or tert-butyl hydroperoxide react in an inert solvent.

Step Q4 is the process of preparing compounds of general formula (LXI) and (LXII), which process is to make the compound of general formula (LVII) and peroxide according to the above-mentioned O1 step in the presence or absence of a base. For example, m-chloroperbenzoic acid, hydrogen peroxide or tert-butyl hydroperoxide react in an inert solvent.

Step Q5 is the process of preparing compounds of general formula (LXIII) and (LXIV), which is to make the compound of general formula (LVIII) and peroxide according to the above-mentioned O1 step in the presence or absence of a base. For example, m-chloroperbenzoic acid, hydrogen peroxide or tert-butyl hydroperoxide react in an inert solvent.

When Z in the compound (I)-(IV) of the present invention is a saturated heterocyclic epoxy group (may have 1-5 substituents α ₁ ), the compound (I) of the present invention can also be synthesized according to the following method- (IV). Method R

In the above formula, R ₁ , R ₂ , R ₃ , W ₁ , W ₂ , X, Y', Z", Z_, A, B and R represent the same meanings as above.

Method R is to prepare a substance in which Z in compound (I) or (IV) of the present invention is a saturated heterocyclic epoxy group (which may have 1-5 substituted moieties α ₁ ) that can be protected, that is, it has the general formula (LXVII ), (LXVIII), (LXIX) and (LXXII) compounds.

Step R1 is a process for preparing a compound of general formula (LXV), which is carried out by reacting a compound of general formula (XLVII) with a compound of general formula (VII) in an inert solvent according to the above step B1.

The R2 step is a process for preparing the compound of the general formula (LXVI), which is carried out by reacting the compound of the general formula (LXV) in an inert solvent according to the above-mentioned B2 step.

R3 step is the process of preparing the compound with general formula (LXVII), which process is according to J.Am.Chem.Soc., 77, 3310 (1955) or Chem.Pharm.Bull.39 (8), 2124-2125 ( 1991), make the compound with general formula (LXVI) and the compound such as 1,2,3,4-tetra-O-acetyl-β-D-glucopyranose corresponding to its substituting part be protected Z group Methyl uronic acid methyl ester (Methyl 1,2,3,4-tetra-O-acetyl-β-D-glucopyranuronate) etc. were reacted in an inert solvent.

R4 step is the process of preparing compounds with general formula (LXVIII), which is according to J.Am.Chem.Soc., 77, 3310 (1955) or Chem.Pharm.Bull.39 (8), 2124-2125 ( 1991), by subjecting a compound of general formula (LXVII) to hydrolysis in an inert solvent.

Step R5 is a process for preparing a compound of general formula (LXIX) by reacting a compound of general formula (LXVIII) with ammonia in an inert solvent according to the above-mentioned step B1.

Step R6 is a process for preparing a compound of general formula (LXX), which is carried out by hydrolyzing the compound of general formula (LXVI) in an inert solvent according to the above step A1.

Step R7 is a process for preparing a compound of general formula (LXXI) by reacting a compound of general formula (LXX) with ammonia in an inert solvent according to the above-mentioned step B1.

The R8 step is a process for preparing compounds of the general formula (LXXII), which is according to J.Am.Chem.Soc., 77, 3310 (1955) or Chem.Pharm.Bull.39 (8), 2124-2125 ( 1991), make the compound with general formula (LXXI) and the compound such as 1,2,3,4-tetra-O-acetyl-beta-D-glucopyranose corresponding to its substituting part be protected Z group Methyl uronic acid methyl ester (Methyl 1,2,3,4-tetra-O-acetyl-β-D-glucopyranuronate) etc. were reacted in an inert solvent.

The R9 step is a process for preparing compounds of the general formula (LXIX), which is according to J.Am.Chem.Soc., 77, 3310 (1955) or Chem.Pharm.Bull.39 (8), 2124-2125 ( 1991), by subjecting a compound of general formula (LXXII) to hydrolysis in an inert solvent.

The compound (I) or (IV) of the present invention wherein Z is a hydroxyl group can be synthesized as follows.

Method S

Method S is a method for preparing the compound represented by the general formula (XXXV)-(XL) in Method N and the compound represented by (XXXVI)-(XLVI) in Method O in which Z is a hydroxyl group.

The method can use the starting material in the N method and the O method, that is, the compound in which Z is a hydroxyl group in the general formula (VI) and the general formula (XXXVII), react according to the method N and the method O, and prepare the compound of the general formula (XXXV) A compound in which Z is a hydroxyl group among the compounds represented by -(XL) and (XLI)-(XLVI).

In addition, the compound (XLVI) in which Z is a hydroxyl group in the compound represented by the general formula (VI) can be prepared according to the above-mentioned step P1.

In addition, it is also possible to replace the compound shown in the above chemical synthesis scheme with a compound whose substituent part is protected, and then obtain the compound shown in the chemical synthesis scheme by removing the protecting group.

For example, when the substituting moiety γ is a hydroxyl group, the above-mentioned chemical synthesis is carried out with the compound whose hydroxyl group is protected, and then the compound shown in the chemical synthesis scheme is obtained by removing the protecting group.

After the reaction, the target compound of each step was collected from the reaction mixture by conventional methods. For example, neutralize the reaction mixture appropriately, and remove the insoluble matter by filtration in the presence of the insoluble matter, add water and an immiscible organic solvent such as ethyl acetate, separate the organic layer containing the target compound, wash with water, etc., and use After drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium bicarbonate, etc., the solvent was distilled off to obtain the target compound. If necessary, the obtained target compound can be separated by conventional methods, such as recrystallization, reprecipitation and other methods commonly used in the separation and purification of organic compounds, using chromatography, and eluting with an appropriate eluent. refined.

Furthermore, the compound of the present invention can also be obtained by a conventional method, for example, the following method.

A compound having physiological activity (for example, the compound described in JP-A-9-295970) is administered to a warm-blooded animal, and after a certain period of time, a biological sample is obtained from the animal. Then, the compound in the biological sample is separated and purified by separation and analysis methods such as column chromatography to obtain the compound of the present invention.

Warm-blooded animals here refer to animals that have the ability to regulate body temperature and basically maintain a constant body temperature regardless of the external temperature, such as mammals such as dogs, monkeys, rabbits, guinea pigs, rats or mice, and poultry such as chickens.

Examples of biological samples here are plasma, urine, feces (bile), liver, kidney, and the like.

The compounds of the present invention having the above general formula (I)-(IV) and their pharmaceutically acceptable salts, their pharmaceutically acceptable esters or their pharmaceutically acceptable amides have excellent PPARγ activation, anti-insulin Sexual improvement, hypoglycemic effect, anti-inflammatory effect, immunomodulatory effect, aldose reductase inhibitory effect, 5-lipoxygenase inhibitory effect, lipid peroxidation inhibitory effect, PPAR activation, anti-osteoporosis effect, Leukotriene antagonism, adipocyteization promotion, cancer cell proliferation inhibition, calcium antagonism, as diabetes, hyperlipidemia, obesity, glucose intolerance, hypertension, fatty liver, diabetic complications (such as retinal disease, kidney disease, neuropathy, cataract, coronary artery disease, etc.), arteriosclerosis, gestational diabetes, polycystic ovary syndrome, cardiovascular disease (such as ischemic heart disease, etc.), non-atherosclerotic or ischemic heart disease Cell damage (such as brain damage caused by stroke, etc.), gout, inflammatory diseases (such as osteoarthritis, pain, fever, rheumatoid arthritis, inflammatory bowel disease, acne, sunburn, psoriasis, eczema, allergies Diseases, asthma, GI ulcer, cachexia, autoimmune disease, pancreatitis, etc.), cancer, osteoporosis, cataract, etc. are useful as preventive and/or therapeutic drugs.

Moreover, the compounds of the present invention having the above general formula (I)-(IV) and their pharmaceutically acceptable salts, their pharmaceutically acceptable esters or their pharmaceutically acceptable amides and at least one RXR activator (RXR agonists), alpha-glucosidase inhibitors, aldose reductase inhibitors, biguanides, statins, squalene synthesis inhibitors, fibrates, LDL catabolic accelerators, and angiotensin converting enzymes A pharmaceutical composition consisting of an inhibitor (particularly preferably a preventive and/or therapeutic drug for diabetes or diabetic complications) is also useful.

The compounds of the present invention having the above-mentioned general formula (I)-(IV) and their pharmaceutically acceptable salts, their pharmaceutically acceptable esters or their pharmaceutically acceptable amides are used as the above-mentioned therapeutic drugs or preventive drugs In the case of , it can be taken by itself or mixed with an appropriate pharmaceutically acceptable excipient, diluent, etc., for example, in the form of tablets, capsule preparations, granule preparations, powder preparations or syrup preparations, etc. orally or injections or suppositories, etc. Administration in non-oral form.

These preparations can be produced by well-known methods using additives such as excipients (examples are organic excipients such as derivatives of sugars such as lactose, sucrose, glucose, mannitol, sorbitol, starch derivatives Such as corn starch, potato starch, α-starch, dextrin, cellulose derivatives such as crystalline cellulose, gum arabic, dextran, pullulan; inorganic excipients such as silicate derivatives such as light anhydrous silicic acid , synthetic aluminum silicate, calcium silicate, magnesium metaaluminosilicate, phosphates such as calcium hydrogen phosphate, carbonates such as calcium carbonate, sulfates such as calcium sulfate, etc.), lubricants (examples are stearic acid and stearin Acid metal salts such as calcium stearate, magnesium stearate, talc, colloidal silica, waxes such as honeycomb, spermaceti, boric acid, adipic acid, sulfates such as sodium sulfate, ethylene glycol, fumaric acid, sodium benzoate, DL leucine, fatty acid sodium salts, lauryl sulfates such as sodium lauryl sulfate, magnesium lauryl sulfate, silicic acids such as anhydrous silicic acid, silicic acid hydrate, and the aforementioned starch derivatives), Binders (examples include hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyethylene glycol (Macrogol) and the same compounds as the above-mentioned excipients), disintegrants (examples include fiber Vein derivatives such as low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium, internally cross-linked sodium carboxymethyl cellulose, chemically modified starch-celluloses such as carboxymethyl starch, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone), stabilizers (examples are parabens such as methyl paraben, propyl paraben, alcohols such as chlorobutanol, benzyl Alcohol, phenylethyl alcohol, benzalkonium chloride, phenols such as phenol, cresol, thimerosal thiosalicylate, dehydroacetic acid and sorbic acid), flavoring agents (examples of which are commonly used sweeteners , sour agents, spices, etc.) and diluents, etc.

Dosage varies according to symptoms, age, administration method, etc. For example, in the case of oral administration, the lower limit of each administration is 0.001 mg/kg body weight (preferably 0.01 mg/kg body weight), and the upper limit is 500 mg/kg body weight (preferably 50 mg/kg body weight), in the case of intravenous administration, the lower limit of each administration is 0.005 mg/kg body weight (preferably 0.05 mg/kg body weight), and the upper limit is 50 mg/kg body weight (preferably 5 mg/kg body weight) ), it is desirable to administer once to several times a day according to the symptoms.

[Best Mode for Carrying Out the Invention]

The present invention will be further described in detail below through examples, reference examples and test examples, but the scope of the present invention is not limited thereto.

Example 1

3-[4-[6-(4-adamantan-1-ylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2-(4-fluoro Benzyloxy) methyl propionate (the methyl ester of compound No. 1-1)

0.8 g of 3-[4-[4-(4-(adamantane-1-yl)phenoxy)-2-(N-tert-butoxycarbonyl-N-methylamino)phenylaminocarbonylmethyl Oxy]phenyl]-2-(4-fluorobenzyl)propanoic acid methyl ester and 20 ml of 4N hydrogen chloride/dioxane solution were stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, the residue was neutralized with sodium bicarbonate, and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. Ethyl acetate was evaporated under reduced pressure, a 4:1 mixed solvent of hexane:ethyl acetate was added to the residue, and the precipitated crystals were collected by filtration to obtain 0.43 g of the title compound with a melting point of 118-120°C.

Example 2

3-[4-[6-(4-adamantan-1-ylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2-(4-fluoro Benzyloxy) propionic acid (compound No. 1-1)

0.25g of 3-[4-[6-(4-adamantan-1-ylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2- A mixture of methyl (4-fluorobenzyloxy)propionate, 2 ml of 2N aqueous sodium hydroxide solution and 5 ml of methanol was stirred at room temperature for 2 hours. Add 5 ml of tetrahydrofuran and stir for a further 4 hours. The reaction mixture was poured into water, neutralized with hydrochloric acid and aqueous sodium bicarbonate, extracted with ethyl acetate, the extract was washed with saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. Ethyl acetate was removed by evaporation under reduced pressure, ethyl acetate was added to the residue, and the precipitated crystals were taken out by filtration to obtain 0.23 g of the title compound having a melting point of 148-149°C.

Example 3

3-[4-[6-(3,5-di-tert-butyl-4-hydroxyphenylthio)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2- Methyl (4-fluorobenzyloxy)propionate (the methyl ester of compound No. 1-86)

Use 0.50 g of 3-[4-[4-(3,5-di-tert-butyl-4-hydroxyphenylthio)-2-(N-tert-butoxycarbonyl-N-methylamino)phenylamino Carbonylmethoxy] phenyl]-2-(4-fluorobenzyl) methyl propionate and the 4N hydrogen chloride/dioxane solution of 10ml, react, process by embodiment 1, obtain 0.24g Rf value is 0.15 ( Silica gel thin layer chromatography, hexane:ethyl acetate 3:1) the title compound.

Example 4

3-[4-[6-(3,5-di-tert-butyl-4-hydroxyphenylthio)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2- (4-Fluorobenzyloxy)propanoic acid (compound No. 1-86)

Use 0.22 g of 3-[4-[6-(3,5-di-tert-butyl-4-hydroxyphenylthio)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl ]-2-(4-fluorobenzyloxy)methyl propionate, 2ml of 2N aqueous sodium hydroxide solution and 5ml of methanol were reacted and treated according to Example 2 to obtain 0.13g of the target compound with a melting point of 40-46°C.

Example 5

Methyl 4-(1-methyl-6-methoxy-1H-benzimidazol-2-ylmethoxy)phenyllactate (the methyl ester of compound number 1-177 listed)

Using 4.5g of 4-(5,5-dimethyl-2-oxodioxolan-3-ylmethyl)phenoxyacetic acid-N-[2-(N-tert-butoxycarbonyl-N- Methylamino)-4-methoxyphenyl] amide, the 4N hydrogen chloride/dioxane solution of the methyl alcohol of 40ml and 40ml, carry out reaction, process by embodiment 1, carry out again with dimethylformamide/ethyl acetate Crystallization gave 1.84 g of the title compound with a melting point of 169-170°C.

Example 6

4-(1-Methyl-6-methoxy-1H-benzimidazol-2-ylmethoxy)phenyl lactate hydrochloride (the hydrochloride salt of compound No. 1-177)

A mixture of 0.2 g of 4-(1-methyl-6-methoxy-1H-benzimidazol-2-ylmethoxy)phenyllactate), 5 ml of methanol and 10 ml of 4N hydrogen chloride/dioxane solution Stir at room temperature for 2 hours. The reaction solution was concentrated, and the precipitated crystals were collected by filtration and washed with a mixture of methanol/ether to obtain 0.2 g of the target compound with a melting point of 193-195°C.

Example 7

4-(1-Methyl-6-methoxy-1H-benzimidazol-2-ylmethoxy)phenyllactic acid (compound No. 1-177)

A mixture of 0.15 g of 4-(1-methyl-6-methoxy-1H-benzimidazol-2-ylmethoxy)phenyl lactate, 2 ml of concentrated hydrochloric acid and 2 ml of dioxane solution was heated to reflux for 3 Hour. The reaction solution was concentrated, dioxane was added, water was removed by azeotropy, and the precipitated crystals were taken out by filtration to obtain 0.15 g of the target compound with a melting point of 216-218°C. Example 8

2-ethoxy-3-[4-(1-methyl-6-methoxy-1H-benzimidazol-2-ylmethoxy)phenyl]propionic acid methyl ester (compound number 1- 179 methyl ester)

0.6g methyl 4-(1-methyl-6-methoxy-1H-benzimidazol-2-ylmethoxy)phenyl lactate, 0.52ml ethyl iodide, 0.88g silver oxide and 15ml dimethyl The mixture of methyl formamide was heated for 4.5 hours and stirred overnight at room temperature. The insoluble matter was removed by filtration from the reaction solution, the filtrate was concentrated, water was added, extracted with ethyl acetate, the extract was washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. Ethyl acetate was evaporated under reduced pressure, and the residue was chromatographed on silica gel (hexane:ethyl acetate 2:3) to obtain 0.15 g of the title compound with a melting point of 88-92°C.

Example 9

2-Ethoxy-3-[4-(1-methyl-6-methoxy-1H-benzimidazol-2-ylmethoxy)phenyl]propionate hydrochloride (compound number 1 -179 hydrochloride)

0.17g methyl 2-ethoxy-3-[4-(1-methyl-6-methoxy-1H-benzimidazol-2-ylmethoxy)phenyl]propionate, 2ml concentrated hydrochloric acid The mixture with 2 ml of dioxane solution was heated at reflux for 1.5 hours. The reaction solution was concentrated, dioxane was added, water was removed by azeotropy, and the precipitated crystals were taken out by filtration to obtain 0.16 g of the target compound with a melting point of 143-146°C. Example 10

4-[6-(4-Hydroxy-2,3,5-trimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl lactate (cited Methyl ester of compound number 1-170)

Use 5.98g of 4-(5,5-dimethyl-2-oxodioxolan-3-ylmethyl)phenoxyacetic acid-N-[2-(N-tert-butoxycarbonyl-N-methyl) Amino)-4-(4-methoxymethoxy-2,3,5-trimethylphenoxy)phenyl]amide, 50ml methanol and 50ml 4N hydrogen chloride/dioxane solution, according to Example 1 The reaction was carried out, the solvent was evaporated under reduced pressure, the residue was neutralized with sodium bicarbonate, extracted with ethyl acetate, the extract was washed with saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. Ethyl acetate was evaporated under reduced pressure, and the residue was chromatographed on silica gel (hexane:ethyl acetate: 1:2→1:3) to obtain 3.15 g of the title compound with a melting point of 172-173°C.

Example 11

Methyl 4-[6-(4-hydroxy-2,3,5-trimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl lactate hydrochloride (the hydrochloride salt of the methyl ester of the cited compound number 1-170)

Using 0.2 g methyl 4-[6-(4-hydroxy-2,3,5-trimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyllactate , 2ml of methanol and 5ml of 4N hydrogen chloride/dioxane solution were reacted and treated according to Example 6 to obtain 0.195g of the target compound with a melting point of 113-119°C. Example 12

4-[6-(3,5-di-tert-butyl-4-hydroxyphenylthio)-1-methyl-1H-benzimidazol-2-ylmethylhydrogen]phenyllactate (compound Methyl esters numbered 1-87)

Using 5.1g of 4-(5,5-dimethyl-2-oxodioxolan-3-ylmethyl)phenoxyacetic acid-N-[2-(N-tert-butoxycarbonyl-N-methyl) Amino)-4-(3,5-di-tert-butyl-4-hydroxyphenylthio) phenyl]amide, 40ml methanol and 40ml 4N hydrogen chloride/dioxane solution, react and process according to Example 1, to obtain 2.6 g of the target compound with a melting point of 155-156°C.

Example 13

Methyl 4-[6-(3,5-di-tert-butyl-4-hydroxyphenylthio)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl lactate hydrochloride ( The hydrochloride of the methyl ester of the cited compound number 1-87)

Use 0.2g 4-[6-(3,5-di-tert-butyl-4-hydroxyphenylthio)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl lactate methyl ester and 10ml of 4N hydrogen chloride/dioxane solution was reacted and treated according to Example 6 to obtain 0.19g of the target compound with a melting point of 135-139°C.

Example 14

4-(6-Methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenylalanine methyl ester (the methyl ester of compound No. 3-177)

2.42g 2-azido-3-[4-(6-methoxyl-1-methyl-1H-benzimidazol-2-yl)phenyl]propionic acid methyl ester was dissolved in 20ml tetrahydrofuran, added 1.6 g triphenylphosphine, stirred at room temperature for 1.5 hours, added 5 ml of water, and further stirred at 60°C for 1 hour. After adding water to the reaction mixture, extraction was performed with ethyl acetate, the extract was washed with saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. Ethyl acetate was evaporated under reduced pressure, and the residue was chromatographed on silica gel (ethyl acetate → tetrahydrofuran) to obtain 1.63 g of the title compound having a melting point of 108-111°C.

Example 15

N-(2-benzoylphenyl)-4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenylalanine methyl ester (compound Methyl esters No. 3-188)

1.1g 4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenylalanine methyl ester, 0.7g 2-benzoylcyclohexanone, 0.2 A mixture of 10% palladium on carbon and 15 ml anisole was heated to reflux for 21 hours. The insolubles were removed by filtration, anisole was evaporated from the filtrate under reduced pressure, and the residue was chromatographed by silica gel chromatography (hexane:ethyl acetate was 1:2) to obtain 0.95 g with an Rf value of 0.51 (silica gel Thin layer chromatography, hexane:ethyl acetate 1:3) the target compound. Example 16

N-(2-benzoylphenyl)-4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenylalanine methyl ester hydrochloride ( The hydrochloride of the methyl ester of the cited compound number 3-188)

Use 0.45g N-(2-benzoylphenyl)-4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenylalanine methyl ester, 2ml of methanol and 10ml of 4N hydrogen chloride/dioxane solution were reacted and treated according to Example 6 to obtain 0.195g of the target compound with a melting point of 132-136°C.

Example 17

N-(2-benzoylphenyl)-4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenylalanine (compound number 3 -188)

Use 0.45g N-(2-benzoylphenyl)-4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenylalanine methyl ester, 5ml of concentrated hydrochloric acid and 5ml of dioxane solution were reacted and treated as in Example 6 to obtain 0.44g of the target compound with a melting point of 140-146°C. Example 18

4-(6-Methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenylalanine dihydrochloride (the dihydrochloride salt of compound No. 3-177)

Use 0.12g 4-(6-methoxyl-1-methyl-1H-benzimidazol-2-ylmethoxy)phenylalanine methyl ester, 2ml concentrated hydrochloric acid and 2ml dioxane solution, according to the implementation Example 6 was reacted and treated to obtain 0.11 g of the target compound with a melting point of 235-237° C. (decomposition).

Example 19

4-[6-(4-Amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]-N-(2-benzoylbenzene base) phenylalanine methyl ester (the methyl ester of compound number 3-285 cited)

Using 1.05g 4-[2-(N-tert-butoxycarbonyl-N-methylamino)-4-(4-tert-butoxycarbonylamino-3,5-dimethylphenoxy)phenylamino Carbonylmethoxyl group]-N-(2-benzoylphenyl) phenylalanine methyl ester, 5ml methyl alcohol and 10ml 4N hydrogen chloride/dioxane solution, carry out reaction, process according to embodiment 6 (liquid chromatography LiChroprep NH 2 (MERCK), hexane: ethyl acetate is 1: 2), obtains 0.62g Rf value 0.39 (silica gel thin layer chromatography (LiChroprepNH (MERCK)), hexane: ethyl acetate is 1: 2) target compound. Example 20

4-[6-(4-Amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]-N-(2-benzoylbenzene Base) phenylalanine dihydrochloride (the dihydrochloride salt of compound No. 3-285)

0.25g 4-[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]-N-(2-benzene A mixture of formylphenyl)phenylalanine methyl ester, 0.04 g lithium hydroxide monohydrate, 5 ml tetrahydrofuran and 2 ml water was stirred at room temperature for 3 hours. After neutralizing with 1N hydrochloric acid, water was added, extracted with ethyl acetate, the extract was washed with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. Ethyl acetate was removed by evaporation under reduced pressure, and the residue was chromatographed on silica gel (LiChroprepDIOL (MERCK), ethyl acetate), and the resulting yellow substance was dissolved in 3 ml of tetrahydrofuran, and 1 ml of 4N hydrogen chloride/dioxane was added. solution, and the precipitated crystals were taken out by filtration to obtain 0.11 g of the target compound with a melting point of 148-155°C.

Example 21

4-[6-[4-(4-trifluoromethylphenylureido)-3,5-dimethylphenoxy]-1-methyl-1H-benzimidazol-2-ylmethoxy ]-N-(2-benzoylphenyl)phenylalanine methyl ester (the methyl ester of compound No. 3-299)

0.35g 4-[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]-N-(2-benzene Formylphenyl) phenylalanine methyl ester was dissolved in 5ml tetrahydrofuran, 0.1ml 4-trifluorophenylisocyanate was added, and stirred at room temperature for 20 hours. The solvent was removed by evaporation under reduced pressure, and the residue was chromatographed by silica gel chromatography (LiChroprepDIOL (MERCK), hexane:ethyl acetate 1:3) to obtain 0.43 g with an Rf value of 0.59 (silica gel thin layer chromatography, LiChroprepDIOL (MERCK), ethyl acetate) target compound.

Example 22

4-{6-[4-(4-trifluoromethylphenylureido)-3,5-dimethylphenoxy]-1-methyl-1H-benzimidazol-2-ylmethoxy }-N-(2-benzoylphenyl)phenylalanine (compound No. 3-299)

0.4g 4-(6-[4-(4-trifluoromethylphenylureido)-3,5-dimethylphenoxy]-1-methyl-1H-benzimidazol-2-yl A mixture of methoxy}-N-(2-benzoylphenyl)phenylalanine methyl ester, 0.042g of lithium hydroxide monohydrate, 5ml of tetrahydrofuran and 2ml of water was stirred at room temperature for 4 hours and placed for 2 day. After neutralizing with 1N hydrochloric acid, water was added, extracted with ethyl acetate, the extract was washed with saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. The ethyl acetate was evaporated under reduced pressure, Dissolve the obtained yellow substance in 10ml of tetrahydrofuran, add 4ml of 4N hydrogen chloride/dioxane solution, evaporate the solvent under reduced pressure, add ether, and take out the precipitated crystals by filtration to obtain 0.38g of 165-172°C melting point target compound.

Example 23

N-methylsulfonyl-4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenylalanine methyl ester (the methyl of compound number 3-261 base ester)

Dissolve 0.2 g of 4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenylalanine methyl ester in 6 ml tetrahydrofuran and 3 ml dimethylformamide, Then 0.09 ml of pyridine and 0.14 g of methanesulfonic anhydride were added, and stirred at room temperature for 3 hours. After adding water to the reaction mixture, extraction was performed with ethyl acetate, the extract was washed with saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. Ethyl acetate was concentrated under reduced pressure, and the precipitated crystals were taken out by filtration to obtain 0.12 g of the title compound having a melting point of 168-171°C.

Example 24

N-methylsulfonyl-4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenylalanine hydrochloride (the compound number 3-261 Hydrochloride)

Use 0.11g N-methylsulfonyl-4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenylalanine methyl ester, 1ml concentrated hydrochloric acid and 4ml di Oxane was reacted and treated according to Example 6 to obtain 0.11 g of the target compound with a melting point of 214-217° C. (decomposition). Example 25

3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-mercaptopropionic acid ethyl ester (compound No. 5-1 ethyl ester hydrochloride)

8.0g 5-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)benzyl]thiazolidine-2,4-dione hydrochloride was suspended in In 150ml of ethanol, add an aqueous solution of 30g of potassium hydroxide in 150ml of water, and stir at 75°C for 4 hours. The reaction mixture was poured into ice water, acidified with hydrochloric acid, and stirred for 30 minutes. The precipitate was taken out by filtration, washed with water and dried under reduced pressure.

The obtained powder was dissolved in 100 ml of absolute ethanol and 200 ml of 4N HCl/dioxane, and left at room temperature for 2 days. The solvent was evaporated from the reaction mixture under reduced pressure, water was added, neutralized with aqueous sodium bicarbonate, extracted with ethyl acetate, the extract was washed with saturated aqueous sodium chloride, and carried out on anhydrous sodium sulfate. dry. The solvent was removed by evaporation under reduced pressure and the resulting residue was chromatographed on a silica gel column [ _LChroprepNH2 (Merck), ethyl acetate:hexane 4:1 as eluent] to give an Rf value of 3.93 g It was the target compound at 0.45 [silica gel thin-layer chromatography (LChroprepNH ₂ (Merck)), ethyl acetate/n-hexane 5/1 as the spectrum solvent].

Example 26

3-[4-(6-Methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionic acid ethyl ester (compound number 5- 4 ethyl ester)

3.9g ethyl 3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-mercaptopropionate was dissolved in 80ml tetrahydrofuran, Then 0.87ml of iodomethane and 1.94ml of triethylamine were added and left overnight. Then add 0.6ml iodomethane and 1.3ml triethylamine, and stir for 70 minutes. The solvent was evaporated from the reaction mixture under reduced pressure, water was added, extraction was performed with ethyl acetate, the extract was washed with saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure, and the resulting residue was chromatographed by silica gel column chromatography (ethyl acetate: hexane was 1: 1 as eluent) to obtain 3.58 g with an Rf value of 0.45 [silica gel thin-layer chromatography method (spectrum solvent: ethyl acetate/n-hexane = 1/1) of the target compound. After standing at room temperature, it becomes a solid with a melting point of 74-76°C.

Example 27

3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionic acid (the compound number 5-4 Hydrochloride)

Dissolve 2.0 g of ethyl 3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionate in 25 ml of tetrahydrofuran , then added 0.42 g of potassium hydroxide monohydrate and 5 ml of dimethylformamide, followed by stirring at room temperature for 2 hours. 0.42 g of potassium hydroxide monohydrate and 5 ml of water were added, and after stirring at room temperature for 20 minutes, 5 ml of dimethylformamide was added and stirred at room temperature for 1 hour. After standing overnight, 0.42 g of potassium hydroxide, 5 ml of water, and 5 ml of dimethylformamide were further added, followed by stirring at 75° C. for 8 hours. Pour the reaction mixture into 800ml of 1N hydrochloric acid, stir for 30 minutes, remove the precipitate by filtration, wash with water, acetone and ethyl acetate in sequence, and dry under reduced pressure to obtain 1.27g of the target compound with a melting point of 201-206°C . Example 28

3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionic acid amide (compound number 5-4 amides)

Add 1.1g of 3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionic acid into 15ml tetrahydrofuran and 15ml di methylformamide, and then after adding 0.82 ml of triethylamine and 0.28 ml of ethyl chloroformate, stirred at room temperature for 30 minutes. 5 ml of ammonia water (28%) was added, stirred at room temperature for 15 minutes, and left overnight. The solvent was evaporated from the reaction mixture under reduced pressure, water was added, extraction was performed with ethyl acetate, the extract was washed with saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure, the resulting residue was washed with ethyl acetate, and recrystallized from a mixed solvent of ethanol and ethyl acetate to obtain 0.45 g of the title compound having a melting point of 204-206°C.

Example 29

3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylsulfinylpropionic acid amide (compound number 5 Amide of -21) and

3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylsulfonylpropionic acid amide (compound number 5- Amide of 22)

0.35g 3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionic acid amide was added to 8ml sulfolane and 15 ml of dichloromethane, then added 84 mg of sodium bicarbonate and 0.22 g of m-chloroperbenzoic acid, and stirred at room temperature for 1.5 hours. 5 ml of 2% aqueous sodium sulfate solution was added to the reaction mixture, and stirred at room temperature for 10 minutes. Water was added to the reaction mixture, extracted with ethyl acetate, the extract was washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation under reduced pressure, and the obtained residue was subjected to silica gel column chromatography [LChroprepNH ₂ (Merck) (ethyl acetate:ethanol 15:1 as eluent)] to obtain 3.93 g of 0.45 [silica gel thin layer chromatography LChroprepNH ₂ (Merck) (ethyl acetate/n-hexane: 5/1 as the spectrum solvent)] the target compound.

Wash with ethyl acetate and recrystallize with a mixed solvent of ethanol and ethyl acetate to obtain 0.12 g of 3-[4-(6-methoxy-1-methyl-1H-benzene with a melting point of 233-236°C) Imidazol-2-ylmethoxy)phenyl]-2-methylsulfonylpropionic acid amide and 0.14g of 3-[4-(6-methoxy-1-methyl- 1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylsulfinylpropionic acid amide.

Example 30

3-[4-[6-(β-D-glucopyranosyloxyuronic acid)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2-methyl Thiopropionic acid amide (the amide of the listed compound number 5-48)

5-[4-[6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione hydrochloride at 5 mg/kg After oral administration of salt to rats, the bile of rats was collected from 0-24 hours, and after freeze-drying, the residue was subjected to ODS column chromatography (filling agent is ODS-A 120-S75, produced by YMC Company, using water ( Use 1mol/l hydrochloric acid to adjust the pH to 4)/acetonitrile as the eluent, and carry out rough purification according to 100/0-60/40 segmental stripping). Further use HPLC to refine the part containing metabolites to obtain the target compound (m/z 548[M+H] ⁺ ESI-MS, Q-TOF hybrid MS/MS spectrometer (produced by Micromass (Micromass) UK company) )).

HPLC conditions (gradient method)

HPLC device: Hitachi HPLC gradient system (L-6200 smart pump, D-2500 chromatographic integrator, L-4000 UV detector)

Chromatographic column: YMC-Pack ODS-A A-312 (length 150mm, inner diameter 6.0mm, particle size 5μm, product of YMC Corporation)

Flow rate: 1.0ml/min

Temperature: room temperature

Retention time: 13.9 minutes

Mobile phase: mobile phase A: water (0.01% trifluoroacetic acid solution), mobile phase B: acetonitrile (0.01% trifluoroacetic acid solution)

Gradient condition:

0 minutes - Mobile Phase A: 88%, Mobile Phase B: 12%

30 minutes - mobile phase A: 40%, mobile phase B: 60%

35 minutes - mobile phase A: 10%, mobile phase B: 90%

40 minutes - mobile phase A: 10%, mobile phase B: 90%

Detection: UV detection: detection wavelength 220nm

     RI detection: 14C detection

Detector: Flow-one/beta-Radiomatic525TR (produced by パツカ-ド (Packard) Co., Ltd.)

Liquid scintillator: ULTIMZ-FLO M (manufactured by パツカ-ド (Packard) Co., Ltd.)

  Flow rate: 3.0ml/min

Example 31

3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylsulfinylpropionic acid (compound number 5- Amide of 21)

Using the same method as in Example 30, the labeled compound (m/z 403 [M+H] ⁺ (ESI-MS; Q-TOF hybrid MS/MS spectrometer (produced by Micromass) UK)) was obtained. .

Retention time: 18.2 minutes

Example 32

3-[4-(6-Hydroxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionic acid amide (the amide of compound number 5-26 )

Using the same method as in Example 30, the labeled compound (m/z 372[M+H] ⁺ (ESI-MS; Q-TOF hybrid MS/MS spectrometer (manufactured by Micromass) UK)) was obtained. .

Retention time: 18.2 minutes.

Example 33

3-[4-[6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2-methylsulfinylpropionic acid amide (compound number 5 Amide of -21)

5-[4-[6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione hydrochloride at 5 mg/kg After oral administration of salt to rats, the urine of rats was collected from 0-24 hours, and after lyophilization, the residue was chromatographed with ODS column (filling agent is ODS-A 120-S75, produced by YMC Company, using water (with The hydrochloric acid of 1mol/l adjusts the pH to 4)/acetonitrile as eluent, according to 100/0-60/40 step-by-step stripping) for rough refining. Further use HPLC to refine the part containing metabolites to obtain the target compound (m/z 402 [M+H] ⁺ ESI-MS, Q-TOF hybrid MS/MS spectrometer (produced by Micromass (Micromass) UK company) )).

HPLC conditions (gradient method)

HPLC device: Hitachi HPLC gradient system (L-6200 smart pump, D-2500 chromatographic integrator, L-4000 UV detector)

Chromatographic column: YMC-Pack ODS-A A-312 (length 150mm, inner diameter 6.0mm, particle size 5μm, produced by YMC Corporation)

Flow rate: 1.0ml/min

Temperature: room temperature

Retention time: 17.2 minutes

Mobile phase: mobile phase A: water (0.01% trifluoroacetic acid solution), mobile phase B: acetonitrile (0.01% trifluoroacetic acid solution)

Gradient condition:

0 minutes - Mobile Phase A: 88%, Mobile Phase B: 12%

30 minutes - mobile phase A: 40%, mobile phase B: 60%

35 minutes - mobile phase A: 10%, mobile phase B: 90%

40 minutes - mobile phase A: 10%, mobile phase B: 90%

Detection: UV detection: detection wavelength 220nm

     RI detection: 14C detection

Detector: Flow-one/beta-Radiomatic525TR (manufactured by パッカ-ド (Packard) Co., Ltd.)

Liquid scintillator: ULTIMA-FLO M (manufactured by パツカ-ド (Packard) Co., Ltd.)

Flow rate: 3.0ml/min Example 34

3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylsulfinylpropionic acid (compound number 5- twenty one)

Using the same method as in Example 33, the labeled compound (m/z 403 [M+H] ⁺ (ESI-MS; Q-TOF hybrid MS/MS spectrometer (manufactured by Micromass) UK)) was obtained. .

Retention time: 18.3 minutes.

Example 35

3-[4-[6-(β-D-glucopyranosyloxyuronic acid)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2-mercapto Propion hydrochloride (the hydrochloride salt of the cited compound No. 5-45)

1-O-[1-methyl-2-[4-(2,4-thiazolidinedione-5-ylmethyl)phenoxymethyl]-1H-benzimidazol-2-yl]- The β-D-glucopyranosyloxyuronic acid was suspended in ethanol, and an aqueous solution of potassium hydroxide was added thereto, followed by stirring. The reaction mixture was poured into ice water, acidified with hydrochloric acid, and stirred. The precipitate was taken out by filtration, washed with water, and dried under reduced pressure to obtain the target product. Example 36

3-[4-(6-Hydroxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionic acid ethyl ester hydrochloride (compound number 5 -26 ethyl ester hydrochloride)

11g N-{2-[4-(2-methylthio-2-ethoxycarbonylethyl)phenoxyacetylamino]-5-hydroxyphenyl}-N-methylcarbamate tert-butyl A mixture of ester, 50 ml of ethanol and 200 ml of 4N hydrochloric acid in 1,4-dioxane was left overnight at room temperature. The solvent was removed by evaporation, and the precipitated substance was collected by filtration and washed with ethyl acetate to obtain 6.12 g of the title compound as off-white powder with a melting point of 149°C-152°C.

Example 37

3-[4-(6-Hydroxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropion hydrochloride (compound number 5-26 hydrochloride)

Use 6g 3-[4-(6-hydroxyl-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionic acid ethyl ester hydrochloride, 6g hydroxide Potassium, 50ml of N,N-dimethylformamide and 50ml of distilled water were reacted and post-treated according to Example 27 to obtain 2.7g of the target compound in the form of light red powder with a melting point of 195°C-198°C.

Example 38

2-Mercapto-3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]propanamide (the amide of compound No. 5-1)

1.53g 2-acetylthio-3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]propanoic acid, 0.4g anhydrous The mixture of triethylamine, 0.65g ethyl chloroformate, 10ml anhydrous tetrahydrofuran and 10ml anhydrous N,N-dimethylformamide was stirred at room temperature for 1 hour, then 20ml of 28% ammonia solution was added and stirred for another 2 hours . After standing overnight, the reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride, and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation, and the residue was chromatographed by liquid chromatography (LiChroprepNH ₂ (MERCK), ethyl acetate:ethanol: 12:1) to obtain 0.21 g of the target compound as a light yellow powder with a melting point of 204°C-208°C. compound.

Example 39

3-[4-(1-methyl-6-methylthio-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionic acid methyl ester hydrochloride (cited Hydrochloride of the methyl ester of compound number 5-67)

7.14g 3-[4-(1-methyl-6-methylthio-1H-benzimidazol-2-ylmethoxy)phenyl]-2-mercaptopropionic acid methyl ester, 3.78g iodomethane A mixture of 2.69 g of triethylamine and 200 ml of anhydrous tetrahydrofuran was stirred at room temperature for 23 hours. After the reaction mixture was concentrated, water was added, extraction was performed with ethyl acetate, and the extract was dried over anhydrous sodium sulfate. The solvent was evaporated from the extract, and the resulting residue was chromatographed on a silica gel column (hexane: ethyl acetate 1:2), followed by formation of hydrochloride with 4N hydrochloric acid ethyl acetate solution to give 5.75 g The target compound with a melting point of 163-166°C. Example 40

3-[4-(1-Methyl-6-methylthio-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropion hydrochloride (compound No. 5-67 hydrochloride)

5.75g 3-[4-(1-methyl-6-methylthio-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionic acid methyl ester hydrochloride , 100ml of concentrated hydrochloric acid and 100ml of 1,4-dioxane was heated to reflux for 90 minutes. After the reaction liquid was concentrated to dryness, tetrahydrofuran was added to the obtained residue, and ultrasonic waves were irradiated. The insoluble product was taken out by filtration, washed with ethyl acetate, further dissolved in N,N-dimethylformamide, and reprecipitated from ether to obtain 5.02 g of the target compound with a melting point of 193-196°C.

Example 41

3-[4-(1-methyl-6-methylthio-1H-benzimidazol-2-ylmethoxy)phenyl]-2-mercaptopropionic acid methyl ester (compound No. 5-67 methyl ester)

Use 55.9g 2-(N-tert-butoxycarbonyl-N-methylamino)-4-methylthionitrobenzene, 7.25g 10% palladium on carbon and 600ml methanol/1,4-dioxane (1/1) mixed solvent, react and process by reference example 5, obtain 54.8g Rf value is 0.16 (silica gel thin-layer chromatography, hexane: ethyl acetate is 3: 1) crude and refined 2-(N -tert-butoxycarbonyl-N-methylamino)-4-methylthioaniline.

The obtained 54.8g 2-(N-tert-butoxycarbonyl-N-methylamino)-4-methylthioaniline, 64.0g 4-(2,4-dioxthiazolidin-5-ylmethyl ) phenoxyacetic acid, 36.8 g of diethyl cyanophosphate, 22.8 g of triethylamine and 300 ml of anhydrous tetrahydrofuran were stirred at room temperature for 67 hours. The reaction mixture was concentrated, water was added, neutralized with 3N hydrochloric acid and sodium bicarbonate, and extracted with ethyl acetate. After the extract was dried over anhydrous sodium sulfate, the solvent was removed by evaporation, and 150 ml of 4N hydrochloric acid dioxane solution was added to the resulting residue, followed by stirring at room temperature for 15 hours and at 80°C for 5 hours. The reaction mixture was concentrated, neutralized with sodium bicarbonate, extracted with a mixed solvent of ethyl acetate and tetrahydrofuran, and the extract was dried over anhydrous sodium sulfate. Evaporate the solvent from the extract, reprecipitate the resulting residue with N,N-dimethylformamide and ethyl acetate, suspend the obtained precipitate in 4N hydrochloric acid ethyl acetate, and take out the insoluble product by filtration , washed with ethyl acetate and dried. Next, 35.2 g of this intermediate product was dissolved in 300 ml of 28% sodium methoxide/methanol solution and 200 ml of water, and stirred at 80° C. for 90 minutes. After the reaction solution was concentrated, it was acidified with 6N hydrochloric acid, and the precipitated product was collected by filtration, washed with water and ethyl acetate, and dried under reduced pressure. Furthermore, 22.4 g of this intermediate product was dissolved in 150 ml of 4N dioxane hydrochloric acid, 150 ml of methanol was added, and the mixture was stirred at room temperature for 65 hours. The reaction solution was concentrated, neutralized with 5% aqueous sodium bicarbonate solution, and extracted with ethyl acetate. After the extract was dried over anhydrous sodium sulfate, the solvent was removed by evaporation, and the resulting residue was subjected to silica gel column chromatography (hexane:ethyl acetate: 1:3) to obtain 7.49 g of the target compound.

Reference example 1

Methyl 4-(tert-butoxycarbonylmethoxy)phenyllactate

A mixture of 18.5 g of methyl 4-hydroxyphenyl lactate, 14 ml of tert-butyl bromoacetate, 26.0 g of anhydrous potassium carbonate and 300 ml of anhydrous dimethylformamide was stirred at 60°C for 10 hours and left at room temperature for 1 day. The reaction solution was poured into water, extracted with ethyl acetate, washed with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. Ethyl acetate was removed by evaporation under reduced pressure, and the residue was chromatographed by silica gel chromatography (hexane: ethyl acetate was 2:1 → 1:1) to obtain 17.5 g with an Rf value of 0.62 (silica gel thin layer chromatography , hexane: ethyl acetate 1:1) the target compound.

Reference example 2

Methyl 3-[4-(tert-butoxycarbonylmethoxy)phenyl]-2-(4-fluorobenzyloxy)propionate

A mixture of 3.0 g of methyl 4-(tert-butoxycarbonylmethoxy)phenyl lactate, 2.4 ml of 4-fluorobenzyl bromide, 9.0 g of silver oxide and 60 ml of toluene was stirred at 80° C. for 3 hours under a nitrogen atmosphere. After removing the insoluble matter by filtration, toluene was evaporated under reduced pressure, and the residue was chromatographed by silica gel chromatography (hexane: ethyl acetate was 5: 1) to obtain 2.9 g with an Rf value of 0.39 (silica gel thin layer chromatography , hexane: ethyl acetate 3:1) the target compound.

Reference example 3

Methyl 3-[4-(carboxymethoxy)phenyl]-2-(4-fluorobenzyloxy)propionate

Dissolve 2.8 g of methyl 3-[4-(tert-butoxycarbonylmethoxy)phenyl]-2-(4-fluorobenzyloxy)propionate in 50 ml of 4N HCl/dioxane at room temperature Stir for 3 hours. The solvent was evaporated off under reduced pressure to obtain 2.42 g of the target compound with an Rf value of 0.10 (silica gel thin layer chromatography, hexane:ethyl acetate 5:1). Reference example 4

4-(4-adamantan-1-ylphenoxy)-2-(N-tert-butoxycarbonyl-N-methylamino)nitrobenzene

After washing 2.1 g of sodium hydride with hexane, 200 ml of dimethylformamide was added. Add 10.0g 4-(1-adamantyl)phenol under ice-bath condition, stir 1 hour at room temperature. 15.1 g of 4-chloro-2-(N-tert-butoxycarbonyl-N-methylamino)nitrobenzene was added under ice-bath conditions, stirred at room temperature for 2 hours, and left at room temperature for 2 days. After dimethylformamide was evaporated under reduced pressure, water was added to the residue, extraction was performed with ethyl acetate, the extract was washed with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. Ethyl acetate was removed by evaporation under reduced pressure, and the residue was chromatographed by silica gel chromatography (hexane:ethyl acetate was 10:1) to obtain 23.0 g with an Rf value of 0.63 (silica gel thin layer chromatography, hexane: Ethyl acetate 3:1) of the title compound.

Reference example 5

4-(4-Adamantan-1-ylphenoxy)-2-(N-tert-butoxycarbonyl-N-methylamino)aniline

14g 4-(4-adamantan-1-ylphenoxy)-2-(N-tert-butoxycarbonyl-N-methylamino)nitrobenzene, 1.50g 10% palladium carbon and 300ml methanol The mixture was stirred at room temperature and 50° C. for 2 hours in a hydrogen stream, respectively, and after being left overnight at room temperature, it was further stirred at 50° C. for 2 hours. The insoluble matter was removed by filtration, the solvent was evaporated under reduced pressure, and the residue was chromatographed on silica gel (hexane:ethyl acetate: 3:1) to obtain 6.70 g of the target compound with a melting point of 85-90°C. Reference example 6

3-{4-[4-(4-(adamantan-1-yl)phenoxy)-2-(N-tert-butoxycarbonyl-N-methylamino)phenylaminocarbonylmethoxy]benzene Methyl}-2-(4-fluorobenzyl)propionate

To 0.6g 3-[4-(carboxymethoxy)phenyl]-2-(4-fluorobenzyloxy)propionic acid methyl ester, 0.75g 4-(4-adamantan-1-ylphenoxy)- 0.30 ml of diethyl cyanophosphate was added to a solution of 2-(N-tert-butoxycarbonyl-N-methylamino)aniline and 0.28 ml of triethylamine in 15 ml of tetrahydrofuran, and stirred at room temperature for 5 hours. The reaction mixture was poured into water, extracted with ethyl acetate, the extract was washed with saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. Ethyl acetate was evaporated under reduced pressure, and the residue was chromatographed on silica gel (hexane:ethyl acetate 3:1) to obtain 1.08 g of the title compound with a melting point of 52-56°C.

Reference example 7

4-(3,5-di-tert-butyl-4-hydroxyphenylthio)-2-(N-tert-butoxycarbonyl-N-methylamino)nitrobenzene

With 8.0g 3,5-di-tert-butyl-4-hydroxyphenyl mercaptan, 9.62g 4-chloro-2-(N-tert-butoxycarbonyl-N-methylamino)nitrobenzene, 23.2g carbonic acid A mixture of potassium and 150 ml of dimethylformamide was stirred at 80°C for 1 hour. Dimethylformamide was evaporated under reduced pressure, water was added to the residue, extraction was performed with ethyl acetate, the extract was washed with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. Ethyl acetate was evaporated under reduced pressure, and the residue was chromatographed on silica gel (hexane:ethyl acetate: 20:1→10:1) to obtain 12.1 g of the title compound with a melting point of 140-141°C.

Reference example 8

4-(3,5-di-tert-butyl-4-hydroxyphenylthio)-2-(N-tert-butoxycarbonyl-N-methylamino)aniline

Use 9.4g 4-(3,5-di-tert-butyl-4-hydroxyphenylthio)-2-(N-tert-butoxycarbonyl-N-methylamino)nitrobenzene, 9.4g 10% paraffin Palladium carbon and 100ml of methanol were reacted and treated according to Reference Example 5 to obtain 8.82g of the target compound with a melting point of 95-96°C.

Reference example 9

3-{4-[4-(3,5-di-tert-butyl-4-hydroxyphenylthio)-2-(N-tert-butoxycarbonyl-N-methylamino)phenylaminocarbonylmethoxy ]phenyl}-2-(4-fluorobenzyl)propionic acid methyl ester

Using 2.28g 4-(3,5-di-tert-butyl-4-hydroxyphenylthio)-2-(N-tert-butoxycarbonyl-N-methylamino)aniline, 1.75g 3-[4-( Carboxymethoxy) phenyl] -2-(4-fluorobenzyloxy) methyl propionate, 50ml tetrahydrofuran solution of 0.83ml triethylamine and 0.90ml diethyl cyanophosphate, react by reference example 6, Workup gave 0.60 g of the title compound with an Rf value of 0.48 (silica gel thin layer chromatography, hexane:ethyl acetate 3:1). Reference example 10

4-(5,5-Dimethyl-2-oxodioxolan-3-ylmethyl)phenol

After dissolving 30 g of 4-hydroxyphenyl lactic acid in 100 ml of acetone, 10 ml of concentrated sulfuric acid was added dropwise at -50°C, and stirred at room temperature for 4 hours. The reaction mixture was poured into ice water, neutralized with aqueous sodium hydroxide and sodium bicarbonate, extracted with ethyl acetate, washed with saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. Ethyl acetate was removed by evaporation under reduced pressure to obtain 21.6 g of the title compound with an Rf value of 0.34 (silica gel thin layer chromatography, hexane:ethyl acetate 4:1).

Reference example 11

Benzyl 4-(5,5-Dimethyl-2-oxodioxolan-3-ylmethyl)phenoxyacetate

A mixture of 21.5 g 4-(5,5-dimethyl-2-oxodioxolan-3-ylmethyl)phenol, 44 g benzyl bromoacetate, 63 g cesium carbonate and 500 ml acetone was stirred at room temperature for 1.5 hours . The solvent was evaporated under reduced pressure, water was added to the residue, extraction was performed with ethyl acetate, the extract was washed with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. Ethyl acetate was removed by evaporation under reduced pressure, and the residue was chromatographed by silica gel chromatography (hexane:ethyl acetate was 5:1→3:1) to obtain 32.9 g with an Rf value of 0.51 (silica gel thin layer chromatography , hexane: ethyl acetate 4:1) the target compound. Reference example 12

4-(5,5-Dimethyl-2-oxodioxolan-3-ylmethyl)phenoxyacetic acid

A mixture of 15g 4-(5,5-dimethyl-2-oxodioxolan-3-ylmethyl)phenoxyacetate, 2g 5% palladium carbon and 150ml dioxane in hydrogen The mixture was stirred at room temperature for 1.5 hours under atmosphere. The insoluble matter was removed by filtration, the filtrate was concentrated under reduced pressure, and the precipitated crystals were obtained by filtration, washed with isopropyl ether, and dried to obtain 9.42 g of the target compound with a melting point of 138-139°C.

Reference example 13

4-(5,5-Dimethyl-2-oxodioxolan-3-ylmethyl)phenoxyacetic acid-N-[2-(N-tert-butoxycarbonyl-N-methylamino) -4-methoxyphenyl]amide

Using 2.5g 2-(N-tert-butoxycarbonyl-N-methylamino)-4-methoxyaniline, 3.0g 4-(5,5-dimethyl-2-oxodioxolane-3- Base methyl) phenoxyacetic acid, 1.66ml triethylamine, 100ml tetrahydrofuran and 1.82ml diethyl cyanophosphate, react and process by reference example 6, obtain 4.56g Rf value is 0.17 (silica gel thin-layer chromatography, Hexane:ethyl acetate 3:1) the target compound. Reference example 14

4-Methoxymethoxy-2,3,5-trimethylphenol

Dissolve 35.4 g of 4-hydroxy-2,3,5-trimethylphenyl pivalate in 300 ml of tetrahydrofuran, add 8.51 g of sodium hydride at room temperature, and stir for 30 minutes. 15.7 g of methoxychloromethane was added dropwise to the solution, followed by stirring at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and water was added to the residue, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. Ethyl acetate was removed by evaporation under reduced pressure, the residue was dissolved in 100 ml of methanol, and a solution of 16.8 g of potassium hydroxide in 100 ml of methanol was added dropwise, followed by stirring at room temperature. The solvent was removed by evaporation under reduced pressure, water was added to the residue, and after neutralization with 3N hydrochloric acid, extraction was carried out with ethyl acetate and dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure, and the residue was chromatographed by silica gel chromatography (hexane: ethyl acetate 5:1) to obtain 27.5 g with an Rf value of 0.16 (silica gel thin layer chromatography, hexane: ethyl acetate). The ester is 4:1) of the target compound.

Reference example 15

2-(N-tert-butoxycarbonyl-N-methylamino)-4-(4-methoxymethoxy-2,3,6-trimethylphenoxy)nitrobenzene

27.5g of 4-methoxymethoxy-2,3,5-trimethylphenol was dissolved in 300ml of dimethylformamide, 6.11g of 55% sodium hydride was added, and stirred for 1 hour. A small amount of 40.1 g of 4-chloro-2-(N-tert-butoxycarbonyl-N-methylamino)nitrobenzene was added in batches to the solution, and stirred at 120° C. for 2 hours. The solvent was evaporated under reduced pressure, and water was added to the residue, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. Ethyl acetate was removed by evaporation under reduced pressure, and the residue was chromatographed by silica gel chromatography (hexane:ethyl acetate was 5:1) to obtain 57.0 g with an Rf value of 0.55 (silica gel thin layer chromatography, hexane: Ethyl acetate 4:1) of the title compound.

Reference example 16

2-(N-tert-butoxycarbonyl-N-methylamino)-4-(4-methoxymethoxy-2,3,6-trimethylphenoxy)aniline

Use 57.0g 2-(N-tert-butoxycarbonyl-N-methylamino)-4-(4-methoxymethoxy-2,3,6-trimethylphenoxy)nitrobenzene, 3g of 10% palladium-on-carbon and 500ml of methanol were reacted and processed according to Reference Example 5 to obtain 52.5g of the target product with an Rf value of 0.31 (silica gel thin-layer chromatography, hexane: ethyl acetate was 3: 1).

Reference example 17

4-(5,5-Dimethyl-2-oxodioxolan-3-ylmethyl)phenoxyacetic acid N-[2-(N-tert-butoxycarbonyl-N-methylamino)- 4-(4-Methoxymethoxy-2,3,5-trimethylphenoxy)phenyl]amide

Use 4.0g 2-(N-tert-butoxycarbonyl-N-methylamino)-4-(4-methoxymethoxy-2,3,6-trimethylphenoxy)aniline, 3.23g 4-(5,5-Dimethyl-2-oxodioxolan-3-ylmethyl)phenoxyacetic acid, 1.73ml triethylamine, 150ml tetrahydrofuran and 1.9ml diethyl cyanophosphate, according to reference Example 6 was reacted and processed to obtain 6g of the target compound with an Rf value of 0.25 (silica gel thin-layer chromatography, hexane: ethyl acetate was 3: 1).

Reference example 18

4-(5,5-Dimethyl-2-oxodioxolan-3-ylmethyl)phenoxyacetic acid N-[2-(N-tert-butoxycarbonyl-N-methylamino)- 4-(3,5-di-tert-butyl-4-hydroxyphenylthio)phenyl]amide

Use 4.5g 4-(3,5-di-tert-butyl-4-hydroxyphenylthio)-2-(N-tert-butoxycarbonyl-N-methylamino)aniline, 3.0g 4-(5,5 -Dimethyl-2-oxodioxolan-3-ylmethyl)phenoxyacetic acid, 1.66ml triethylamine, 100ml tetrahydrofuran and 1.82ml diethyl cyanophosphate, react and process according to Reference Example 6 , Obtain 5.15g of the target compound with an Rf value of 0.38 (silica gel thin layer chromatography, hexane:ethyl acetate is 2:1).

Reference example 19

2-Azido-3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-yl)phenyl]propanoic acid methyl ester

2.5g 4-(1-methyl-6-methoxy-1H-benzimidazol-2-ylmethoxy)methyl phenyl lactate, 2.3ml diphenylphosphoric azide, 4.8ml azobis A mixture of diethyl formate, 2.8 g of triphenylphosphine and 100 ml of tetrahydrofuran was stirred at room temperature for 1 hour and left overnight. The solvent was evaporated under reduced pressure, and the residue was chromatographed on silica gel (hexane:ethyl acetate 2:1) to obtain 2.1 g of the title compound having a melting point of 105-107°C.

Reference example 20

N-(2-Benzoylphenyl)tyrosine methyl ester

A mixture of 4.8g tyrosine methyl ester hydrochloride, 5.0g 2-benzoylcyclohexanone, 1.0g 10% palladium on carbon, 2.9ml triethylamine and 70ml anisole was heated to reflux for 20 hours. Insoluble matter was removed by filtration, water was added to the filtrate, extraction was performed with ethyl acetate, the extract was washed with saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. Ethyl acetate was removed by evaporation under reduced pressure, and the residue was chromatographed by silica gel chromatography (hexane:ethyl acetate 3:1) to obtain 1.83 g with an Rf value of 0.39 (silica gel thin layer chromatography, hexane: Ethyl acetate 3:1) of the title compound.

Reference example 21

4-tert-butoxycarbonylmethoxy-N-(2-benzoylphenyl)alanine methyl ester

A mixture of 0.97 g of methyl N-(2-benzoylphenyl)tyrosine, 0.55 ml of tert-butyl bromoacetate, 1.14 g of cesium carbonate and 15 ml of acetone was stirred at room temperature for 1.5 hours and left overnight. Water was added to the reaction mixture, extracted with ethyl acetate, the extract was washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. Ethyl acetate was removed by evaporation under reduced pressure to obtain 1.42 g of the target compound with an Rf value of 0.65 (silica gel thin-layer chromatography, hexane:ethyl acetate 3:1). Reference example 22

4-Carboxymethoxy-N-(2-benzoylphenyl)alanine methyl ester

A mixture of 1.4 g of 4-tert-butoxycarbonylmethoxy-N-(2-benzoylphenyl)alanine methyl ester, 10 ml of 4N hydrogen chloride/dioxane solution, and 10 ml of dioxane was stirred at room temperature 3 hours, leave overnight. The solvent was evaporated under reduced pressure, toluene was added, the toluene was evaporated again under reduced pressure, and the residue was chromatographed on silica gel ('LiChroprepDIOL' (MERCK), hexane:ethyl acetate 2:1→1:1) Chromatography gave 0.87 g of the title compound with an Rf value of 0.53 (silica gel thin layer chromatography, hexane:ethyl acetate 3:2).

Reference example 23

2-(N-tert-butoxycarbonyl-N-methylamino)-4-(4-amino-3,5-dimethylphenoxy)nitrobenzene

Add 1.10 g of 4-amino-3,5-dimethylphenol to a suspension of 30 ml of anhydrous N,N-dimethylformamide containing 0.35 g of sodium hydride (55% by weight), and stir at room temperature for 15 minutes . Next, 2.29 g of 4-chloro-2-(N-tert-butoxycarbonyl-N-methylamino)nitrobenzene was added in small portions to the mixture, and stirred at 120° C. for 1 hour. After completion of the reaction, the solvent was removed by evaporation, water was added, and extraction was performed with ethyl acetate. The extract was dried with anhydrous sodium sulfate, and after the solvent was evaporated, the residue obtained was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/3) to obtain 2-27g Rf value 0.24 (silica gel thin layer chromatography, ethyl acetate: n-hexane ratio 1:3) of the target compound.

Reference example 24

2-(N-tert-butoxycarbonyl-N-methylamino)-4-(4-tert-butoxycarbonylamino-3,5-dimethylphenoxy)nitrobenzene

2.27g 2-(N-tert-butoxycarbonyl-N-methylamino)-4-(4-amino-3,5-dimethylphenoxy)nitrobenzene, 1.28g di-tert-butyl dicarbonate A mixture of the ester, 0.59 g of triethylamine and 20 ml of anhydrous tetrahydrofuran was heated at reflux for 6 hours. The solvent was evaporated from the reaction mixture, water was added, and extraction was performed with ethyl acetate. After drying the extract with anhydrous sodium sulfate, the solvent was removed by evaporation, and the resulting residue was purified by silica gel column chromatography (ethyl acetate: hexane: 1:10) to obtain 1.74 g of the target compound.

Reference example 25

2-(N-tert-butoxycarbonyl-N-methylamino)-4-(4-tert-butoxycarbonylamino-3,5-dimethylphenoxy)aniline

Use 1.71g 2-(N-tert-butoxycarbonyl-N-methylamino)-4-(4-tert-butoxycarbonylamino-3,5-dimethylphenoxy)nitrobenzene, 100ml methanol And 0.2g 10% palladium on carbon, react, process by reference example 5, obtain the target compound of 1.56g Rf value 0.14 (silica gel thin-layer chromatography, ethyl acetate: hexane is 1: 3).

Reference example 26

4-[2-(N-tert-butoxycarbonyl-N-methylamino)-4-(4-tert-butoxycarbonylamino-3,5-dimethylphenoxy)phenylaminocarbonylmethoxy base]-N-(2-benzoylphenyl)phenylalanine methyl ester

Use 0.69g 2-(N-tert-butoxycarbonyl-N-methylamino)-4-(4-tert-butoxycarbonylamino-3,5-dimethylphenoxy)aniline, 0.85g 4- Carboxymethoxy-N-(2-benzoylphenyl)alanine methyl ester, 0.3ml triethylamine, 20ml tetrahydrofuran and 0.33ml diethyl cyanophosphate were reacted and processed according to Reference Example 6 to obtain 1.06 g of the target compound with an Rf value of 0.93 (silica gel thin layer chromatography, ethyl acetate).

Reference example 27

1-O-[1-methyl-2-[4-(2,4-thiazolidinedion-5-ylmethyl)phenoxymethyl]-1H-benzimidazol-2-yl]-β -D-glucopyranosyloxyuronic acid

In nitrobenzene, add 5-[4-(6-hydroxyl-1-methyl-1H-benzimidazol-2-ylmethoxy)benzyl]thiazolidine-2,4-dione hydrochloride, 1,2,3,4-Tetra-O-acetyl-β-D-pyranuronic acid methyl ester and toluenesulfonic acid were stirred while heating under reduced pressure. After the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography to obtain the protected form of the target product. The protected body was added to methanol, and an aqueous sodium hydroxide solution was added dropwise under ice-bath conditions, followed by stirring after the dropwise addition. Sodium chloride was added to the reaction solution to make it saturated, and the solution was acidified with hydrochloric acid, followed by extraction with ethyl acetate. Ethyl acetate was removed by evaporation under reduced pressure, followed by purification by column chromatography to obtain the target product.

Example 28

5-[4-(6-Hydroxy-1-methyl-1H-benzimidazol-2-ylmethoxy)benzyl]thiazolidine-2,4-dione hydrochloride

0.43g N-(2-amino-5-hydroxyphenyl)-N-methylcarbamate tert-butyl ester, 0.51g5-(4-carboxymethoxybenzyl)thiazolidine-2,4-dione, A mixture of 0.29 g of diethylcyanophosphonate (DEPC), 0.18 g of triethylamine and 20 ml of tetrahydrofuran was stirred at room temperature for 8 hours. The solvent was evaporated from the reaction mixture under reduced pressure, water was added, extraction was performed with ethyl acetate, and the extract was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was chromatographed by silica gel column chromatography (ethyl acetate: hexane 3: 2 as eluent) to obtain 0.75 g of N-{5-hydroxyl-2- [4-(2,4-Dioxythiazolidin-5-ylmethyl)phenoxymethylcarbonylamino]phenyl}-N-methylcarbamate tert-butyl ester.

The obtained 0.75g N-{5-hydroxyl-2-[4-(2,4-dioxthiazolidin-5-ylmethyl)phenoxymethylcarbonylamino]phenyl}-N-methylamino Tert-butyl formate was suspended in 10 ml of 4N HCl in dioxane and left at room temperature for 19 hours. The solvent was concentrated under reduced pressure, ethyl acetate was added, and after ultrasonic treatment, the insoluble matter was filtered out and dried to obtain 0.52 g of the target compound with a melting point of 217-220°C.

Reference example 29

N-(5-Benzyloxy-2-nitrophenyl)-N-methylcarbamate tert-butyl ester

A mixture of 5.24 g of sodium hydride (55%, oily), 13 g of benzyl alcohol and 150 ml of anhydrous N,N-dimethylformamide was stirred at room temperature for 30 minutes. Next, add 28.7g N-(5-chloro-2-nitrophenyl)-N-methylcarbamate tert-butyl ester at room temperature, stir for 18 hours, evaporate the solvent, dilute with water and dilute with ethyl acetate Do the extraction. The extract was washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate. The solvent was removed by evaporation, and the resulting residue was subjected to column chromatography (silica gel, ethyl acetate:n-hexane ratio 1:10) to obtain 29.2 g of the title compound as yellow crystals with a melting point of 108-110°C.

Reference example 30

tert-butyl N-(2-amino-5-hydroxyphenyl)-N-methylcarbamate

A mixture of 15g N-(5-benzyloxy-2-nitrophenyl)-N-methylcarbamate tert-butyl ester, 3g10% palladium-on-carbon catalyst, 150ml toluene and 150ml methanol was heated in a hydrogen atmosphere at room temperature Stir for 12.5 hours. Remove 10% palladium-on-carbon catalysts by filtration from the reaction mixture, and evaporate the solvent from the filtrate to obtain 12.3 g of brown oily targets with an Rf value of 0.15 (silica gel thin-layer chromatography, ethyl acetate:n-hexane is 1:4). compound. Reference example 31

3-(4-Hydroxyphenyl)-2-mercaptopropionic acid ethyl ester

A mixture of 100 g of 5-(4-acetoxybenzyl)thiazolidine-2,4-dione, 150 g of potassium hydroxide, 500 ml of distilled water and 500 ml of ethanol was stirred at 75° C. for 2.5 hours. Another 250 g of potassium hydroxide was added under ice-cooling conditions, and the mixture was further stirred at 75° C. for 2 hours.

After standing overnight, the reaction mixture was concentrated to about 300ml, diluted with ice water and adjusted to pH 3 with concentrated hydrochloric acid aqueous solution, then extracted with ethyl acetate, the extract was washed with saturated aqueous sodium chloride solution, and dissolved in anhydrous sulfuric acid Dry on magnesium. The solvent was removed by evaporation from the extract to obtain an oily residue. The residue was dissolved in 500 ml of absolute ethanol, and 500 ml of 4N hydrochloric acid 1,4-dioxane solution was added at room temperature for 2 days. After the solvent was removed by evaporation, the residue was chromatographed by liquid chromatography (silica gel, ethyl acetate: n-hexane 1: 3) to obtain 50.1 g with an Rf value of 0.87 (silica gel thin layer chromatography, ethyl acetate: n-hexane Alkanes 1:1) the light yellow oily target compound.

Reference example 32

3-(4-Hydroxyphenyl)-2-methylthiopropanoic acid ethyl ester

A mixture of 30 g of ethyl 3-(4-hydroxyphenyl)-2-mercaptopropionate, 28.4 g of iodomethane, 20.2 g of triethylamine and 150 ml of tetrahydrofuran was stirred at room temperature for 7 hours. The solvent was removed by evaporation, diluted with water and extracted with toluene. The extract was washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was removed by evaporation to obtain 30.3 g of the title compound as a pale yellow oil with an Rf value of 0.37 (silica gel thin layer chromatography, ethyl acetate:n-hexane ratio 1:4).

Reference example 33

Ethyl 3-(4-tert-butoxycarbonylmethoxyphenyl)-2-methylthiopropionate

Use 14g 3-(4-hydroxyphenyl)-2-methylthiopropionate ethyl ester, 28.5g cesium carbonate, 20g bromoacetate tert-butyl and 200ml acetonitrile, carry out reaction and aftertreatment according to reference example 21, obtain 24.3g The target compound in light yellow oily form with an Rf value of 0.46 (silica gel thin layer chromatography, ethyl acetate: n-hexane ratio 1:7).

Reference example 34

3-(4-Carboxymethoxyphenyl)-2-methylthiopropanoic acid ethyl ester

Use 24g 3-(4-tert-butoxycarbonylmethoxyphenyl)-2-methylthiopropionate ethyl ester and 150ml 4N hydrochloric acid 1,4-dioxane solution, carry out reaction and aftertreatment by reference example 3 , to obtain 11.9 g of the target compound in milky white powder form with a melting point of 77°C-78°C.

Reference example 35

N-[2-[4-(2-Methylthio-2-ethoxycarbonylethyl)phenoxyacetylamino]-5-hydroxyphenyl]-N-methylcarbamate tert-butyl

Use 12.2g N-(2-amino-5-hydroxyphenyl)-N-methylcarbamate tert-butyl ester, 12.2g 3-(4-carboxymethoxyphenyl)-2-methylthiopropionic acid ethyl Ester, 9.79g diethyl cyanophosphate, 6.1g triethylamine and 250ml anhydrous tetrahydrofuran, carry out reaction and aftertreatment by reference example 6, obtain 11.1g Rf value is 0.14 (silica gel thin-layer chromatography, ethyl acetate: n-Hexane 1:2) yellow oily target compound.

Reference example 36

2-(N-tert-butoxycarbonyl-N-methylamino)-4-methylthionitrobenzene

A mixture of 57.3g of 4-chloro-2-(N-tert-butoxycarbonyl-N-methylamino)nitrobenzene, 21.0g of sodium thiomethoxide and 400ml of anhydrous N,N-dimethylformamide was Stir at room temperature for 23 hours. After completion of the reaction, the solvent was removed by evaporation, water was added, and extraction was performed with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and after removing the solvent by evaporation, n-hexane was added to the obtained residue, which was irradiated with ultrasonic waves. The insoluble product was obtained by filtration and washed with n-hexane to obtain 55.9 g of the target compound with a melting point of 114-117°C. Reference example 37

2-Acetylthio-3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]propanoic acid

To 1.5g 2-mercapto-3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl] propionate hydrochloride, 0.87 Add 0.56 g of anhydrous acetic acid to a mixture of 5 g of pyridine, 30 ml of tetrahydrofuran and 30 ml of N,N-dimethylformamide, stir for 5 hours, and then stand for 36 hours. The solvent was removed by evaporation, and the precipitate was filtered and washed with ethyl acetate to obtain 1.55 g of the title compound as a pale yellow powder having a melting point of 209°C-214°C.

[Test example] Hypoglycemic effect

Blood was collected from the tail vein of diabetic KK mice (4-5 months old) to measure their blood glucose levels. Next, the mice were grouped according to the same average value of the blood glucose level of the mice in each group (4 in each group), and then the content of the test compound was adjusted to 0.01% mouse powder feed (F-1, ship Bridge Farm) were fed to the mice for 3 days. The mouse group fed with the test compound was used as the drug administration group. The group fed the powdered feed not containing the test compound was used as a control group. Three days later, blood was collected from the tail vein of the mice, and the glucose concentration in the plasma obtained by centrifugation was measured with a glucose analyzer (Glucoloader, A&T Company). Calculate the average blood sugar lowering rate according to the formula.

Blood sugar lowering rate (%)=(average blood sugar level of control group-average blood sugar level of drug administration group)×100/blood sugar level of control group [Table 6] Test compound Blood sugar lowering rate (%) compound of embodiment 2 58.5

4 40.8

9 48.4

16 32.1

20 40.0

It is evident from the above results that the compounds of the present invention have excellent blood sugar lowering effects. [Preparation Example] (1) Capsule preparation

The compound of Example 2 10mg

Lactose 110mg

  Corn Starch                                          

Magnesium stearate 2mg

                                                               

The powders of the above-mentioned components are fully mixed, and sieved with a sieve of 60 mesh (the purpose standard is according to Tyler standard). 180 mg of the obtained powder was weighed out, and packed into a gelatin capsule (No. 3) to prepare a capsule preparation. (2) Tablets

The compound of Example 2 10mg

Lactose 85mg

  Corn Starch                                                                      

  Microcrystalline Cellulose                                      

Magnesium stearate 1mg

                                                               

The powders of the above-mentioned ingredients are thoroughly mixed, and compressed into tablets with a weight of 150 mg. These tablets may be coated with sugar or a film, if desired.

(3) Granular preparations

The compound of Example 2 10mg

Lactose 839mg

                                                               

                                               

                                      

The powders of the above components are fully mixed, moistened with pure water, granulated with a basket granulator, and dried to obtain a granule preparation.

[industrial availability]

The compounds of the present invention having the above-mentioned general formulas (I)-(IV) and their pharmaceutically acceptable salts, their pharmaceutically acceptable esters or their pharmaceutically acceptable amides have excellent effects of improving insulin resistance, Hypoglycemic effect, anti-inflammatory effect, immunomodulatory effect, aldose reductase inhibitory effect, 5-lipoxygenase inhibitory effect, lipid peroxidation production inhibitory effect, PPAR activation effect, anti-osteoporosis effect, leukotriene antagonism Effects, promotion of adipocytes, inhibition of cancer cell proliferation, calcium antagonism, as diabetes, hyperlipidemia, obesity, glucose intolerance, hypertension, fatty liver, diabetes complications (such as retinopathy, nephropathy, neuropathy, cataract, coronary artery disease, etc.), arteriosclerosis, gestational diabetes, polycystic ovary syndrome, cardiovascular disease (such as ischemic heart disease, etc.), cell damage caused by non-atherosclerotic or ischemic heart disease (such as brain damage caused by stroke, etc.), gout, inflammatory diseases (such as osteoarthritis, pain, fever, rheumatoid arthritis, inflammatory bowel disease, acne, sunburn, psoriasis, eczema, allergic diseases, asthma , GI ulcer, cachexia, autoimmune disease, pancreatitis, etc.), cancer, osteoporosis, cataract, etc., are useful as prophylactic and/or therapeutic drugs.

Moreover, the compound of the present invention having the above-mentioned general formula (I)-(IV) and its pharmaceutically acceptable salt, its pharmaceutically acceptable ester or its pharmaceutically acceptable amide and at least one α-glucose Drug combinations consisting of glycosidase inhibitors, aldose reductase inhibitors, biguanides, statins, squalene synthesis inhibitors, fibrates, LDL catabolic accelerators, angiotensin-converting enzyme inhibitors, and RXR activators Drugs (particularly preferably drugs for the prevention and/or treatment of diabetes or diabetic complications) are also useful.

Claims (68)

1. Insulin resistance improvers, blood sugar lowering agents, immunomodulators, aldose reductase inhibitors, 5-lipoxygenase inhibitors, lipid peroxidation production inhibitors, PPAR activators, leukotriene antagonists, hydroxyl Adipocyteization promoter or calcium antagonist, the agent contains α-substituted carboxylic acid derivatives with general formula (I), their pharmaceutically acceptable esters or their pharmaceutically acceptable amides or their pharmaceutically acceptable accepted salt as an active ingredient, in: R ₁ , R ₂ and R ₃ are the same or different, and represent (i) hydrogen atom, (ii) C ₁ -C ₆ alkyl group, (iii) C ₆ -C ₁₀ aryl group (may have 1-5 following substitutions moiety α ₁ ), (iv) C ₇ -C ₁₆ aralkyl (the aryl group may have 1-5 substituent moieties α ₁ described below), (v) C ₁ -C ₆ alkylsulfonyl, (vi ) C ₁ -C ₆ haloalkylsulfonyl, (vii) C ₆ -C ₁₀ arylsulfonyl (may have 1-5 substituents α ₁ ) or (viii) C ₇ -C ₁₆ aralkylsulfonyl an acyl group (the aryl group may have 1-5 substituent moieties α ₁ described below), A represents a nitrogen atom or =CH-group, B represents an oxygen atom or a sulfur atom, W ₁ represents a C ₁ -C ₈ alkylene group, W ₂ represents a single bond or a C ₁ -C ₈ alkylene group, X represents (i) hydrogen atom, (ii) C ₁ -C ₆ alkyl, (iii) C ₁ -C ₆ haloalkyl, (iv) C ₁ -C ₆ alkoxy, (v) halogen atom, (vi ) hydroxyl group, (vii) cyano group, (viii) nitro group, (ix) C ₃ -C ₁₀ cycloalkyl group, (x) C ₆ -C ₁₀ aryl group (may have 1-5 substituent moieties β as follows) , (xi) C ₇ -C ₁₆ aralkyl (the aryl may have 1-5 substituents β as described below), (xii) C ₁ -C ₇ aliphatic acyl, (xiii) C ₄ -C ₁₁ Cycloalkylcarbonyl, (xiv) C ₇ -C ₁₁ arylcarbonyl (may have 1-5 following substituent moieties β), (xv) C ₈ -C ₁₇ aralkylcarbonyl (may have 1 on aryl -5 substituent moieties β below), (xvi) monocyclic heteroaryl ring carbonyl (may have 1 to 5 substituent moieties β below), (xvii) carbamoyl, (xviii) C ₇ -C ₁₁ Arylaminocarbonyl (the aryl group may have 1-5 substituents β below) or (xix) amino (can have 1 or 2 substituents β below), Y represents an oxygen atom or an S(O)p group (p represents an integer of 0-2 in the formula), Z ₁ represents (i) hydrogen atom, (ii) C ₁ -C ₆ alkyl group, (iii) C ₁ -C ₆ alkoxy group, (iv) C ₁ -C ₆ alkylthio group, (v) halogen atom, (vi) C ₆ -C ₁₀ aryl (may have 1-5 substituents α ₁ described below), (vii) C ₇ -C ₁₆ aralkyl (may have 1-5 substituents described below on aryl Moiety α ₁ ), (viii) C ₆ -C ₁₀ aryloxy group (may have 1-5 substituent moieties α ₁ described below), (ix) C ₇ -C ₁₆ aralkyloxy group (may have 1-5 of the following substituted moieties α ₁ ), (x) C ₃ -C ₁₀ cycloalkoxy, (xi) C ₃ -C ₁₀ cycloalkylthio, (xii) saturated heterocyclic oxy group (may have 1 -5 substituted moieties α ₁ ), (xiii) monocyclic heteroaryl epoxy group (may have 1-5 substituted moieties α ₁ ), (xiv) C ₆ -C ₁₀ arylthio ( may have 1 to 5 of the following substituent moieties α ₁ ), (xv) C ₇ -C ₁₆ aralkylthio (may have 1 to 5 of the following substituent moieties α ₁ on the aryl group), (xvi) saturated hetero Cyclothio group (may have 1 to 5 substituents α ₁ described below), (xvii) monocyclic heteroaryl ring thio group (may have 1 to 5 substituents α ₁ described below), (xviii) amino ( may have 1 or 2 of the following substituted moieties (α ₁ ) or (xix) hydroxyl groups, The substituent moiety _α1 represents (i) C ₁ -C ₆ alkyl, (ii) C ₁ -C ₆ haloalkyl, (iii) C ₁ -C ₆ alkoxy, (iv) halogen atom, (v) Hydroxy, (vi) cyano, (vii) nitro, (viii) C ₃ -C ₁₀ cycloalkyl, (ix) C ₆ -C ₁₀ aryl (may have 1 to 5 substituents β below), (x) C ₇ -C ₁₆ aralkyl (the aryl may have 1-5 substituents β as described below), (xi)) C ₁ -C ₇ aliphatic acyl, (xii) C ₄ -C ₁₁ Cycloalkylcarbonyl, (xiii) C ₇ -C ₁₁ arylcarbonyl (may have 1-5 following substituent moieties β), (xiv) C ₈ -C ₁₇ aralkylcarbonyl (may have 1- 5 of the following substituent moieties β), (xv) monocyclic heteroaryl ring carbonyl (may have 1 to 5 of the following substituting moieties β), (xvi) carbamoyl, (xvii) C ₇ -C ₁₁ aryl Aminocarbonyl (can have 1-5 substituted moieties β as described below on the aryl group), (xviii) amino (may have 1 or 2 substituted moieties β as described below) or (xix) carboxyl, The substituent moiety β represents (i) C ₁ -C ₁₀ alkyl group, (ii) halogen atom, (iii) C ₆ -C ₁₀ aryl group (may have 1-5 substituent moieties γ below), (iv) C ₇ -C ₁₆ aralkyl (the aryl may have 1-5 substituents γ as follows), (v) C ₁ -C ₇ aliphatic acyl, (vi) C ₇ -C ₁₁ arylcarbonyl (can Having 1-5 of the following substituents γ), (vii) C ₈ -C ₁₇ aralkylcarbonyl (the aryl may have 1-5 of the following substituting γ), (viii) C ₄ -C ₁₁ Cycloalkylcarbonyl, (ix) monocyclic heteroaryl ring carbonyl (may have 1 to 5 substituent moieties γ described below), (x) carbamoyl or (xi) C ₇ -C ₁₁ arylaminocarbonyl ( On the aryl group, there may be 1-5 substituent moieties γ) described below, The substituted moiety γ represents a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group, a halogen atom or a hydroxyl group. 2. The α-substituted carboxylic acid derivative, its pharmaceutically acceptable ester or its pharmaceutically acceptable amide or its pharmaceutically acceptable salt as claimed in claim 1 as an active ingredient insulin resistance improving agent, blood sugar Lowering agents, immunomodulators, aldose reductase inhibitors, 5-lipoxygenase inhibitors, lipid peroxidation production inhibitors, PPAR activators, leukotriene antagonists, hydroxyadipocyteization promoters, or calcium antagonists ,in: R ₁ , R ₂ and R ₃ are the same or different, and represent (i) hydrogen atom, (ii) C ₁ -C ₄ alkyl group, (iii) phenyl group (may have 1 substituted moiety α ₁ ), (iv) benzene C ₁ -C ₂ alkyl (may have 1-3 substituent moieties α ₁ on phenyl) or (v) C ₁ -C ₂ alkylsulfonyl. 3. The α-substituted carboxylic acid derivative, its pharmaceutically acceptable ester or its pharmaceutically acceptable amide or its pharmaceutically acceptable salt as claimed in claim 1 as an active ingredient insulin resistance improving agent, blood sugar Lowering agents, immunomodulators, aldose reductase inhibitors, 5-lipoxygenase inhibitors, lipid peroxidation production inhibitors, PPAR activators, leukotriene antagonists, hydroxyadipocyteization promoters, or calcium antagonists ,in: R ₁ , R ₂ and R ₃ are the same or different, and represent (i) hydrogen atom, (ii) C ₁ -C ₄ alkyl group or (iii) benzyl group (may have 1 substituent moiety α ₁ on the phenyl group) . 4. The insulin resistance improving agent containing α-substituted carboxylic acid derivatives, their pharmaceutically acceptable esters or their pharmaceutically acceptable amides or their pharmaceutically acceptable salts as active ingredients, blood sugar as claimed in claim 1 Lowering agents, immunomodulators, aldose reductase inhibitors, 5-lipoxygenase inhibitors, lipid peroxidation production inhibitors, PPAR activators, leukotriene antagonists, hydroxyadipocyteization promoters, or calcium antagonists ,in: R ₁ represents a C ₁ -C ₂ alkyl group, R ₂ represents a hydrogen atom, R ₃ represents a C ₁ -C ₄ alkyl group or a phenyl C ₁ -C ₄ alkyl group (the phenyl group may have one substituent α ₁ ). 5. An α-substituted carboxylic acid derivative, a pharmaceutically acceptable ester thereof, or a pharmaceutically acceptable amide thereof or a pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient for improving insulin resistance, blood sugar Lowering agents, immunomodulators, aldose reductase inhibitors, 5-lipoxygenase inhibitors, lipid peroxidation production inhibitors, PPAR activators, leukotriene antagonists, hydroxyadipocyteization promoters, or calcium antagonists ,in: R ₁ represents a C ₁ -C ₂ alkyl group, R ₂ represents a hydrogen atom, and R ₃ represents a hydrogen atom. 6. The insulin resistance improving agent containing α-substituted carboxylic acid derivatives, their pharmaceutically acceptable esters or their pharmaceutically acceptable amides or their pharmaceutically acceptable salts as an active ingredient according to claims 1-5 , hypoglycemic agents, immunomodulators, aldose reductase inhibitors, 5-lipoxygenase inhibitors, lipid peroxidation production inhibitors, PPAR activators, leukotriene antagonists, hydroxyl adipocyteization promoters, or calcium Antagonists, wherein A represents a =CH-group. 7. The insulin resistance improving agent containing α-substituted carboxylic acid derivatives, their pharmaceutically acceptable esters or their pharmaceutically acceptable amides or their pharmaceutically acceptable salts as an active ingredient according to claims 1-6 , hypoglycemic agents, immunomodulators, aldose reductase inhibitors, 5-lipoxygenase inhibitors, lipid peroxidation production inhibitors, PPAR activators, leukotriene antagonists, hydroxyadipocyteization promoters, or Calcium antagonists, wherein B represents an oxygen atom. 8. The insulin resistance improving agent containing α-substituted carboxylic acid derivatives, their pharmaceutically acceptable esters or their pharmaceutically acceptable amides or their pharmaceutically acceptable salts as an active ingredient according to claims 1-7 , hypoglycemic agents, immunomodulators, aldose reductase inhibitors, 5-lipoxygenase inhibitors, lipid peroxidation production inhibitors, PPAR activators, leukotriene antagonists, hydroxyl adipocyteization promoters, or calcium Antagonist, wherein W ₁ represents C ₁ -C ₄ alkylene. 9. The insulin resistance improving agent containing α-substituted carboxylic acid derivatives, their pharmaceutically acceptable esters or their pharmaceutically acceptable amides or their pharmaceutically acceptable salts as an active ingredient according to claims 1-7 , hypoglycemic agents, immunomodulators, aldose reductase inhibitors, 5-lipoxygenase inhibitors, lipid peroxidation production inhibitors, PPAR activators, leukotriene antagonists, hydroxyl adipocyteization promoters, or calcium Antagonist, wherein W ₁ represents C ₁ -C ₂ alkylene. 10. The insulin resistance improving agent containing α-substituted carboxylic acid derivatives, their pharmaceutically acceptable esters or their pharmaceutically acceptable amides or their pharmaceutically acceptable salts as an active ingredient according to claims 1-9 , hypoglycemic agents, immunomodulators, aldose reductase inhibitors, 5-lipoxygenase inhibitors, lipid peroxidation production inhibitors, PPAR activators, leukotriene antagonists, hydroxyl adipocyteization promoters, or calcium Antagonist, wherein W ₂ represents C ₁ -C ₄ alkylene. 11. The insulin resistance improving agent containing α-substituted carboxylic acid derivatives, their pharmaceutically acceptable esters or their pharmaceutically acceptable amides or their pharmaceutically acceptable salts as active ingredients according to claims 1-9 , hypoglycemic agents, immunomodulators, aldose reductase inhibitors, 5-lipoxygenase inhibitors, lipid peroxidation production inhibitors, PPAR activators, leukotriene antagonists, hydroxyl adipocyteization promoters, or calcium Antagonist, wherein W ₂ represents a methylene group. 12. The insulin resistance improving agent containing α-substituted carboxylic acid derivatives, their pharmaceutically acceptable esters or their pharmaceutically acceptable amides or their pharmaceutically acceptable salts as active ingredients according to claims 1-11 , hypoglycemic agents, immunomodulators, aldose reductase inhibitors, 5-lipoxygenase inhibitors, lipid peroxidation production inhibitors, PPAR activators, leukotriene antagonists, hydroxyl adipocyteization promoters, or calcium Antagonists, of which: X represents (i) a hydrogen atom, (ii) a C ₁ -C ₂ alkyl group, (iii) a halogen atom, (iv) a hydroxyl group, (v) a C ₁ -C ₂ aliphatic acyl group or (vi) an amino group. 13. The insulin resistance improving agent containing α-substituted carboxylic acid derivatives, their pharmaceutically acceptable esters or their pharmaceutically acceptable amides or their pharmaceutically acceptable salts as active ingredients according to claims 1-11 , hypoglycemic agents, immunomodulators, aldose reductase inhibitors, 5-lipoxygenase inhibitors, lipid peroxidation production inhibitors, PPAR activators, leukotriene antagonists, hydroxyl adipocyteization promoters, or calcium Antagonists, wherein X represents a hydrogen atom. 14. The insulin resistance improving agent containing α-substituted carboxylic acid derivatives, their pharmaceutically acceptable esters or their pharmaceutically acceptable amides or their pharmaceutically acceptable salts as active ingredients according to claims 1-13 , hypoglycemic agents, immunomodulators, aldose reductase inhibitors, 5-lipoxygenase inhibitors, lipid peroxidation production inhibitors, PPAR activators, leukotriene antagonists, hydroxyl adipocyteization promoters, or calcium Antagonists, of which: Z ₁ represents (i) C ₁ -C ₂ alkoxy, (ii) C ₁ -C ₂ alkylthio, (iii) halogen atom, (iv) phenoxy (may have 1-5 substituted moieties α ₁ ), (v) saturated heterocyclic oxy group (may have 1-5 substituted moieties α ₁ ), (vi) phenylthio group (may have 1-5 substituted moieties α ₁ ), (vii) saturated heterocyclic thio group (may have 1 to 5 substituted moieties α ₁ ), (viii) amino or (ix) hydroxyl. 15. The insulin resistance improving agent containing α-substituted carboxylic acid derivatives, their pharmaceutically acceptable esters or their pharmaceutically acceptable amides or their pharmaceutically acceptable salts as active ingredients according to claims 1-13 , hypoglycemic agents, immunomodulators, aldose reductase inhibitors, 5-lipoxygenase inhibitors, lipid peroxidation production inhibitors, PPAR activators, leukotriene antagonists, hydroxyadipocyteization promoters, or calcium Antagonists, of which: Z ₁ represents (i) C ₁ -C ₂ alkoxy, (ii) C ₁ -C ₂ alkylthio, (iii) phenoxy (may have 1-5 substituted moieties α ₁ ), (iv) saturated Heterocyclyloxy group (may have 1-5 substituent moieties α ₁ ), (v) phenylthio group (may have 1-5 substituent moieties α ₁ ), or (vi) hydroxyl group. 16. The insulin resistance improving agent containing α-substituted carboxylic acid derivatives, their pharmaceutically acceptable esters or their pharmaceutically acceptable amides or their pharmaceutically acceptable salts as active ingredients according to claims 1-15 , hypoglycemic agents, immunomodulators, aldose reductase inhibitors, 5-lipoxygenase inhibitors, lipid peroxidation production inhibitors, PPAR activators, leukotriene antagonists, hydroxyl adipocyteization promoters, or calcium Antagonists, of which: The substituent moiety _α1 represents (i) C ₁ -C ₄ alkyl, (ii) C ₁ -C ₂ haloalkyl, (iii) C ₁ -C ₂ alkoxy, (iv) halogen atom, (v) hydroxyl, (vi) cyano, (vii) nitro, (viii) adamantyl, (ix) benzoyl (may have 1 substituent β), (x) amino (may have 1 substituent β), or (xi )carboxyl. 17. The insulin resistance improving agent containing α-substituted carboxylic acid derivatives, their pharmaceutically acceptable esters or their pharmaceutically acceptable amides or their pharmaceutically acceptable salts as active ingredients according to claims 1-15 , hypoglycemic agents, immunomodulators, aldose reductase inhibitors, 5-lipoxygenase inhibitors, lipid peroxidation production inhibitors, PPAR activators, leukotriene antagonists, hydroxyl adipocyteization promoters, or calcium Antagonists, of which: The substituent moiety _α1 represents (i) C ₁ -C ₄ alkyl, (ii) halogen atom, (iii) hydroxyl, (iv) adamantyl, (v) benzoyl, (vi) amino (may have 1 substitution Moiety β) or (vii) carboxyl. 18. The insulin resistance improving agent containing α-substituted carboxylic acid derivatives, their pharmaceutically acceptable esters or their pharmaceutically acceptable amides or their pharmaceutically acceptable salts as active ingredients according to claims 1-15 , hypoglycemic agents, immunomodulators, aldose reductase inhibitors, 5-lipoxygenase inhibitors, lipid peroxidation production inhibitors, PPAR activators, leukotriene antagonists, hydroxyadipocyteization promoters, or calcium Antagonists, of which: The substituent moiety α ₁ represents C ₁ -C ₄ alkyl or hydroxyl. 19. The insulin resistance improving agent containing α-substituted carboxylic acid derivatives, their pharmaceutically acceptable esters or their pharmaceutically acceptable amides or their pharmaceutically acceptable salts as active ingredients according to claims 1-15 , hypoglycemic agents, immunomodulators, aldose reductase inhibitors, 5-lipoxygenase inhibitors, lipid peroxidation production inhibitors, PPAR activators, leukotriene antagonists, hydroxyl adipocyteization promoters, or calcium Antagonists, of which: The substituent moiety _α1 represents a halogen atom or an adamantyl group. 20. The insulin resistance improving agent containing α-substituted carboxylic acid derivatives, their pharmaceutically acceptable esters or their pharmaceutically acceptable amides or their pharmaceutically acceptable salts as active ingredients according to claims 1-15 , hypoglycemic agents, immunomodulators, aldose reductase inhibitors, 5-lipoxygenase inhibitors, lipid peroxidation production inhibitors, PPAR activators, leukotriene antagonists, hydroxyadipocyteization promoters, or calcium Antagonists, of which: The substituent moiety α ₁ represents a C ₁ -C ₄ alkyl group, benzoyl group or amino group (may have 1 substituent moiety β). 21. The insulin resistance improving agent containing α-substituted carboxylic acid derivatives, their pharmaceutically acceptable esters or their pharmaceutically acceptable amides or their pharmaceutically acceptable salts as active ingredients according to claims 1-20 , hypoglycemic agents, immunomodulators, aldose reductase inhibitors, 5-lipoxygenase inhibitors, lipid peroxidation production inhibitors, PPAR activators, leukotriene antagonists, hydroxyl adipocyteization promoters, or calcium Antagonists, of which: The substituent β represents (i) a C ₁ -C ₄ alkyl group, (ii) a halogen atom or (iii) a phenylaminocarbonyl group (1 to 3 substituents γ may be present on the phenyl group). 22. The insulin resistance improving agent containing α-substituted carboxylic acid derivatives, their pharmaceutically acceptable esters or their pharmaceutically acceptable amides or their pharmaceutically acceptable salts as active ingredients according to claims 1-20 , hypoglycemic agents, immunomodulators, aldose reductase inhibitors, 5-lipoxygenase inhibitors, lipid peroxidation production inhibitors, PPAR activators, leukotriene antagonists, hydroxyl adipocyteization promoters, or calcium An antagonist wherein the substituent β represents a phenylaminocarbonyl group (may have 1 substituent γ on the phenyl group). 23. The insulin resistance improving agent containing α-substituted carboxylic acid derivatives, their pharmaceutically acceptable esters or their pharmaceutically acceptable amides or their pharmaceutically acceptable salts as active ingredients according to claims 1-22 , hypoglycemic agents, immunomodulators, aldose reductase inhibitors, 5-lipoxygenase inhibitors, lipid peroxidation production inhibitors, PPAR activators, leukotriene antagonists, hydroxyl adipocyteization promoters, or calcium Antagonists, wherein the substituent moiety γ represents a trifluoromethyl group or a halogen atom. 24. The insulin resistance improving agent containing α-substituted carboxylic acid derivatives, their pharmaceutically acceptable esters or their pharmaceutically acceptable amides or their pharmaceutically acceptable salts as active ingredients according to claims 1-22 , hypoglycemic agents, immunomodulators, aldose reductase inhibitors, 5-lipoxygenase inhibitors, lipid peroxidation production inhibitors, PPAR activators, leukotriene antagonists, hydroxyl adipocyteization promoters, or calcium Antagonists wherein the substituent moiety γ represents trifluoromethyl. 25. The insulin resistance improving agent and blood sugar containing α-substituted carboxylic acid derivatives, their pharmaceutically acceptable esters or their pharmaceutically acceptable amides or their pharmaceutically acceptable salts as active ingredients according to claim 1 Lowering agents, immunomodulators, aldose reductase inhibitors, 5-lipoxygenase inhibitors, lipid peroxidation production inhibitors, PPAR activators, leukotriene antagonists, hydroxyadipocyteization promoters, or calcium antagonists ,in: R ₁ , R ₂ and R ₃ are the same or different, and represent (i) hydrogen atom, (ii) C ₁ -C ₄ alkyl group, (iii) phenyl group (may have 1 substituted moiety α ₁ ), (iv) benzene C ₁ -C ₂ alkyl (on the phenyl group may have 1-3 substituents α ₁ described below) or (v) C ₁ -C ₂ alkylsulfonyl, A represents =CH-group, B represents an oxygen atom, W ₁ represents a C ₁ -C ₂ alkylene group, W ₂ represents a C ₁ -C ₂ alkylene group, X represents (i) hydrogen atom, (ii) C ₁ -C ₂ alkyl group, (iii) halogen atom, (iv) hydroxyl group, (v) C ₁ -C ₂ aliphatic acyl group or (vi) amino group, Y represents an oxygen atom or an S(O)p group (p represents an integer of 0-2 in the formula), Z ₁ represents (i) C ₁ -C ₂ alkoxy, (ii) C ₁ -C ₂ alkylthio, (iii) halogen atom, (iv) phenoxy (may have 1-5 substituted moieties α ₁ ), (v) saturated heterocyclic oxy group (may have 1-5 substituted moieties α ₁ ), (vi) phenylthio group (may have 1-5 substituted moieties α ₁ ), (vii) saturated heterocyclic thio group (may have 1-5 substituted moieties α ₁ ), (viii) amino or (ix) hydroxyl, The substituent moiety _α1 represents (i) C ₁ -C ₄ alkyl, (ii) C ₁ -C ₂ haloalkyl, (iii) C ₁ -C ₂ alkoxy, (iv) halogen atom, (v) hydroxyl, (vi) cyano, (vii) nitro, (viii) adamantyl, (ix) benzoyl (may have 1 substituent β), (x) amino (may have 1 substituent β), or (xi )carboxyl, The substituent β represents (i) C ₁ -C ₄ alkyl, (ii) a halogen atom or (iii) phenylaminocarbonyl (1-3 substituents γ may be present on the phenyl group), The substituent γ represents a trifluoromethyl group or a halogen atom. 26. The insulin resistance improving agent and blood sugar containing α-substituted carboxylic acid derivatives, their pharmaceutically acceptable esters or their pharmaceutically acceptable amides or their pharmaceutically acceptable salts as active ingredients according to claim 1 Lowering agents, immunomodulators, aldose reductase inhibitors, 5-lipoxygenase inhibitors, lipid peroxidation production inhibitors, PPAR activators, leukotriene antagonists, hydroxyadipocyteization promoters, or calcium antagonists ,in: R ₁ , R ₂ and R ₃ are the same or different, and represent (i) hydrogen atom, (ii) C ₁ -C ₄ alkyl group or (iii) benzyl group (may have 1 substituent moiety α ₁ on the phenyl group) , A represents =CH-group, B represents an oxygen atom, W ₁ represents a C ₁ -C ₂ alkylene group, W ₂ represents a methylene group, X represents a hydrogen atom, Y represents an oxygen atom or an S(O)p group (p represents an integer of 0-2 in the formula), Z ₁ represents (i) C ₁ -C ₂ alkoxy, (ii) C ₁ -C ₂ alkylthio, (iii) phenoxy (may have 1-5 substituted moieties α ₁ ), (iv) saturated Heterocyclyloxy group (may have 1-5 substituted moieties α ₁ ), (v) phenylthio group (may have 1-5 substituted moieties α ₁ ) or (vi) hydroxyl, The substituent moiety _α1 represents (i) C ₁ -C ₄ alkyl, (ii) halogen atom, (iii) hydroxyl, (iv) adamantyl, (v) benzoyl, (vi) amino (may have 1 substitution moiety β) or (vii) carboxyl, The substituent β represents a phenylaminocarbonyl group (one substituent γ may be present on the phenyl group), The substituent moiety γ represents a trifluoromethyl group. 27. α-substituted carboxylic acid derivatives having the general formula (II), their pharmaceutically acceptable esters or their pharmaceutically acceptable amides or their pharmaceutically acceptable salts, in: R ₁ , R ₂ and R ₃ are the same or different, and represent (i) hydrogen atom, (ii) C ₁ -C ₆ alkyl group, (iii) C ₆ -C ₁₀ aryl group (may have 1-5 following substitutions moiety α ₁ ), (iv) C ₇ -C ₁₆ aralkyl (the aryl group may have 1-5 substituent moieties α ₁ described below), (v) C ₁ -C ₆ alkylsulfonyl, (vi ) C ₁ -C ₆ haloalkylsulfonyl, (vii) C ₆ -C ₁₀ arylsulfonyl (may have 1-5 substituents α ₁ ) or (viii) C ₇ -C ₁₆ aralkylsulfonyl an acyl group (the aryl group may have 1-5 substituent moieties α ₁ described below), A represents a nitrogen atom or =CH-group, B represents an oxygen atom or a sulfur atom, W ₁ represents a C ₁ -C ₈ alkylene group, W ₂ represents a single bond or a C ₁ -C ₈ alkylene group, X represents (i) hydrogen atom, (ii) C ₁ -C ₆ alkyl, (iii) C ₁ -C ₆ haloalkyl, (iv) C ₁ -C ₆ alkoxy, (v) halogen atom, (vi ) hydroxyl group, (vii) cyano group, (viii) nitro group, (ix) C ₃ -C ₁₀ cycloalkyl group, (x) C ₆ -C ₁₀ aryl group (may have 1-5 substituent moieties β as follows) , (xi) C ₇ -C ₁₆ aralkyl (the aryl may have 1-5 substituents β as described below), (xii) C ₁ -C ₇ aliphatic acyl, (xiii) C ₄ -C ₁₁ Cycloalkylcarbonyl, (xiv) C ₇ -C ₁₁ arylcarbonyl (may have 1-5 following substituent moieties β), (xv) C ₈ -C ₁₇ aralkylcarbonyl (may have 1 on aryl -5 substituent moieties β below), (xvi) monocyclic heteroaryl ring carbonyl (may have 1 to 5 substituent moieties β below), (xvii) carbamoyl, (xviii) C ₇ -C ₁₁ Arylaminocarbonyl (the aryl group may have 1-5 substituents β below) or (xix) amino (can have 1 or 2 substituents β below), Y represents an oxygen atom or an S(O)p group (p represents an integer of 0-2 in the formula), Z ₂ represents a saturated heterocyclic group (may have 1-5 substituents α ₁ described below) or a C ₆ -C ₁₀ aryl group (may have 1-5 substituents α ₂ described below), The substituent moiety _α1 represents (i) C ₁ -C ₆ alkyl, (ii) C ₁ -C ₆ haloalkyl, (iii) C ₁ -C ₆ alkoxy, (iv) halogen atom, (v) hydroxyl, (vi) cyano group, (vii) nitro group, (viii) C ₃ -C ₁₀ cycloalkyl group, (ix) C ₆ -C ₁₀ aryl group (may have 1-5 substituent moieties β as follows), (x ) C ₇ -C ₁₆ aralkyl group (the aryl group may have 1-5 substituents β as described below), (xi) C ₁ -C ₇ aliphatic acyl group, (xii) C ₄ -C ₁₁ cycloalkyl group Carbonyl, (xii) C ₇ -C ₁₁ arylcarbonyl (may have 1-5 substituent moieties β below), (xiv) C ₈ -C ₁₇ aralkylcarbonyl (can have 1-5 substituted moieties on aryl The following substituent moiety β), (xv) monocyclic type heteroaryl ring carbonyl (may have 1 to 5 substituent moieties β below), (xvi) carbamoyl group, (xvii) C ₇ -C ₁₁ arylamino group Carbonyl (may have 1-5 substituents β below on the aryl group), (xviii) amino (may have 1 or 2 substituents β below) or (xix) carboxyl, The substituent moiety α ₂ represents (i) C ₃ -C ₁₀ cycloalkyl, (ii) C ₆ -C ₁₀ aryl (may have 1-5 substituent moieties β below), (iii) C ₇ -C ₁₆ aryl Alkyl (the aryl group may have 1-5 substituents β below), (iv) C ₁ -C ₇ aliphatic acyl, (v) C ₄ -C ₁₁ cycloalkylcarbonyl, (vi) C ₇ -C ₁₁ arylcarbonyl (may have 1-5 substituents β below), (vii) C ₈ -C ₁₇ aralkylcarbonyl (may have 1-5 substituents β below on aryl), (viii) monocyclic heteroaryl ring carbonyl (may have 1-5 substituent moieties β as described below) or (ix) C ₇ -C ₁₁ arylaminocarbonyl (may have 1-5 following substituted moieties on the aryl group) replace part β), Substituent moiety β represents (i) C ₁ -C ₁₀ alkyl group, (ii) halogen atom, (iii) C ₆ -C ₁₀ aryl group (may have 1-5 substituent moieties γ below), (iv) C ₇ -C ₁₆ aralkyl (can have 1-5 following substituents γ on aryl), (v) C ₁ -C ₇ aliphatic acyl, (vi) C ₇ -C ₁₁ arylcarbonyl (can have 1 - 5 substituent moieties γ described below), (vii) C ₈ -C ₁₇ aralkylcarbonyl (the aryl group may have 1-5 substituent moieties γ described below), (viii) C ₄ -C ₁₁ cycloalkane (ix) monocyclic heteroaryl ring carbonyl (may have 1-5 substituents γ as follows), (x) carbamoyl or (xi) C ₇ -C ₁₁ arylaminocarbonyl (in aromatic The base may have 1-5 substituent moieties γ) as follows, The substituent moiety γ represents a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group, a halogen atom or a hydroxyl group. 28. the α-substituted carboxylic acid derivative of claim 27, its pharmaceutically acceptable ester or its pharmaceutically acceptable amide or its pharmaceutically acceptable salt, wherein _Z Represent tetrahydropyran (can have 1-5 substituting moieties α ₁ ). 29. the α-substituted carboxylic acid derivative of claim 27, its pharmaceutically acceptable esters or its pharmaceutically acceptable amide or its pharmaceutically acceptable salt, wherein Z Represents phenyl (with ₁ substitution Part α ₂ ). 30. The α-substituted carboxylic acid derivative, its pharmaceutically acceptable ester or its pharmaceutically acceptable amide or its pharmaceutically acceptable salt according to claims 27-29, wherein: Substituent moiety _α2 represents (i) C ₆ -C ₁₀ cycloalkyl, (ii) phenyl (may have 1-3 substituted moieties β), (iii) phenylcarbonyl (may have 1-3 substituted moieties β ) or (iv) monocyclic type heteroaryl ring carbonyl (may have 1 to 3 substituent moieties β). 31. The α-substituted carboxylic acid derivatives, their pharmaceutically acceptable esters or their pharmaceutically acceptable amides or their pharmaceutically acceptable salts according to claims 27-29, wherein the substituted moiety α ₂ represents C ₆ - C ₁₀ cycloalkyl. 32. The α-substituted carboxylic acid derivative, its pharmaceutically acceptable ester or its pharmaceutically acceptable amide or its pharmaceutically acceptable salt according to claim 27, wherein: R ₁ , R ₂ and R ₃ are the same or different, and represent (i) hydrogen atom, (ii) C ₁ -C ₄ alkyl group or (iii) benzyl group (may have 1 substituent moiety α ₁ on the phenyl group) , A represents =CH-group, B represents an oxygen atom, W ₁ represents a C ₁ -C ₂ alkylene group, W ₂ represents a C ₁ -C ₂ alkylene group, X represents a hydrogen atom, Y represents an oxygen atom or an S(O)p group (p represents an integer of 0-2 in the formula), Z ₂ represents tetrahydropyran (may have 1-5 substituted moieties α ₁ ), The substituent moiety _α1 represents a hydroxyl group or a carboxyl group. 33. The α-substituted carboxylic acid derivative, its pharmaceutically acceptable ester or its pharmaceutically acceptable amide or its pharmaceutically acceptable salt according to claim 27, wherein: R ₁ , R ₂ and R ₃ are the same or different, and represent (i) hydrogen atom, (ii) C ₁ -C ₄ alkyl group or (iii) benzyl group (may have 1 substituent moiety α ₁ on the phenyl group) , A represents =CH-group, B represents an oxygen atom, W ₁ represents a C ₁ -C ₂ alkylene group, W ₂ represents a C ₁ -C ₂ alkylene group, X represents a hydrogen atom, Y represents an oxygen atom or an S(O)p group (p represents an integer of 0-2 in the formula), Z ₂ represents phenyl (having 1 substituent moiety α ₂ ), The substituent moiety _α1 represents a halogen atom or an adamantyl group, The substituent moiety _α2 represents an adamantyl group. 34. A medicament comprising the compound according to any one of claims 27-33 as an active ingredient. 35. Insulin resistance improvers, blood sugar lowering agents, immunomodulators, aldose reductase inhibitors, 5-lipoxygenase inhibitors, lipid peroxidation production inhibitors, PPAR activators, leukotriene antagonists, hydroxyl An adipocyteization accelerator or a calcium antagonist comprising the compound according to any one of claims 27-33 as an active ingredient. 36. A preventive and/or therapeutic drug for diabetes, glucose intolerance, neuropathy, cataract, coronary artery disease, gestational diabetes, said drug comprising the compound according to any one of claims 27-33 as an active ingredient. 37. An α-substituted carboxylic acid derivative having the general formula (III), a pharmaceutically acceptable ester thereof, or a pharmaceutically acceptable amide thereof, or a pharmaceutically acceptable salt thereof, in: R ₁ , R ₂ and R ₃ are the same or different, and represent (i) hydrogen atom, (ii) C ₁ -C ₆ alkyl group, (iii) C ₆ -C ₁₀ aryl group (may have 1-5 following substitutions moiety α ₁ ), (iv) C ₇ -C ₁₆ aralkyl (the aryl group may have 1-5 substituent moieties α ₁ described below), (v) C ₁ -C ₆ alkylsulfonyl, (vi ) C ₁ -C ₆ haloalkylsulfonyl, (vii) C ₆ -C ₁₀ arylsulfonyl (may have 1-5 substituents α ₁ ) or (viii) C ₇ -C ₁₆ aralkylsulfonyl an acyl group (the aryl group may have 1-5 substituent moieties α ₁ described below), A represents a nitrogen atom or =CH-group, B represents an oxygen atom or a sulfur atom, W ₁ represents a C ₁ -C ₈ alkylene group, W ₂ represents a single bond or a C ₁ -C ₈ alkylene group, X represents (i) hydrogen atom, (ii) C ₁ -C ₆ alkyl, (iii) C ₁ -C ₆ haloalkyl, (iv) C ₁ -C ₆ alkoxy, (v) halogen atom, (vi ) hydroxyl group, (vii) cyano group, (viii) nitro group, (ix) C ₃ -C ₁₀ cycloalkyl group, (x) C ₆ -C ₁₀ aryl group (may have 1-5 substituent moieties β as follows) , (xi) C ₇ -C ₁₆ aralkyl (the aryl may have 1-5 substituents β as described below), (xii) C ₁ -C ₇ aliphatic acyl, (xiii) C ₄ -C ₁₁ Cycloalkylcarbonyl, (xiv) C ₇ -C ₁₁ arylcarbonyl (may have 1-5 following substituent moieties β), (xv) C ₈ -C ₁₇ aralkylcarbonyl (may have 1 on aryl -5 substituent moieties β below), (xvi) monocyclic heteroaryl ring carbonyl (may have 1 to 5 substituent moieties β below), (xvii) carbamoyl, (xviii) C ₇ -C ₁₁ Arylaminocarbonyl (the aryl group may have 1-5 substituents β below) or (xix) amino (can have 1 or 2 substituents β below), Y represents an oxygen atom or an S(O)p group (p represents an integer of 0-2 in the formula), Z ₃ represents (i) C ₁ -C ₆ alkyl, (ii) C ₆ -C ₁₀ aryl (may have 1-5 substituents α ₁ as follows), (iii) C ₇ -C ₁₆ aralkyl (the aryl group may have 1-5 substituents α ₁ described below), (iv) C ₃ -C ₁₀ cycloalkyl or (v) saturated heterocyclic group (may have 1-5 substituents α described below ₁ ), The substituent moiety _α1 represents (i) C ₁ -C ₆ alkyl, (ii) C ₁ -C ₆ haloalkyl, (iii) C ₁ -C ₆ alkoxy, (iv) halogen atom, (v) hydroxyl, (vi) cyano group, (vii) nitro group, (viii) C ₃ -C ₁₀ cycloalkyl group, (ix) C ₆ -C ₁₀ aryl group (may have 1-5 substituent moieties β as follows), (x ) C ₇ -C ₁₆ aralkyl group (the aryl group may have 1-5 substituents β as described below), (xi) C ₁ -C ₇ aliphatic acyl group, (xii) C ₄ -C ₁₁ cycloalkyl group Carbonyl, (xiii) C ₇ -C ₁₁ arylcarbonyl (may have 1-5 substituent moieties β below), (xiv) C ₈ -C ₁₇ aralkylcarbonyl (can have 1-5 substituted moieties on aryl The following substituent moiety β), (xv) monocyclic type heteroaryl ring carbonyl (may have 1 to 5 substituent moieties β below), (xvi) carbamoyl group, (xvii) C ₇ -C ₁₁ arylamino group Carbonyl (may have 1-5 substituents β below on the aryl group), (xviii) amino (may have 1 or 2 substituents β below) or (xix) carboxyl, Substituent moiety β represents (i) C ₁ -C ₁₀ alkyl group, (ii) halogen atom, (iii) C ₆ -C ₁₀ aryl group (may have 1-5 substituent moieties γ below), (iv) C ₇ -C ₁₆ aralkyl (can have 1-5 following substituents γ on aryl), (v) C ₁ -C ₇ aliphatic acyl, (vi) C ₇ -C ₁₁ arylcarbonyl (can have 1 - 5 substituent moieties γ described below), (vii) C ₈ -C ₁₇ aralkylcarbonyl (the aryl group may have 1-5 substituent moieties γ described below), (viii) C ₄ -C ₁₁ cycloalkane (ix) monocyclic heteroaryl ring carbonyl (may have 1-5 substituents γ as follows), (x) carbamoyl or (xi) C ₇ -C ₁₁ arylaminocarbonyl (in aromatic The base can have 1-5 substituent moieties γ) as follows, The substituent moiety γ represents a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group, a halogen atom or a hydroxyl group. 38. The α-substituted carboxylic acid derivative, its pharmaceutically acceptable ester or its pharmaceutically acceptable amide or its pharmaceutically acceptable salt according to claim 37, wherein: Z ₃ represents (i) C ₁ -C ₄ alkyl, (ii) C ₆ -C ₁₀ aryl (may have 1-3 substituted moieties α ₁ ) or (iii) C ₃ -C ₁₀ cycloalkyl. 39. the α-substituted carboxylic acid derivative of claim 37, its pharmaceutically acceptable esters or its pharmaceutically acceptable amide or its pharmaceutically acceptable salt, wherein _Z Represents phenyl (may have 1- 3 substituted moieties α ₁ ). 40. The α-substituted carboxylic acid derivative, its pharmaceutically acceptable ester or its pharmaceutically acceptable amide or its pharmaceutically acceptable salt according to claim 37, wherein: R ₁ , R ₂ or R ₃ are the same or differently, representing (i) hydrogen atom, (ii) C ₁ -C ₄ alkyl or (iii) benzyl group (may have 1 substituent moiety α ₁ on the phenyl group), A represents =CH-group, B represents an oxygen atom, W ₁ represents a C ₁ -C ₂ alkylene group, W ₂ represents a C ₁ -C ₂ alkylene group, X represents a hydrogen atom, Y represents an oxygen atom or an S(O)p group (p represents an integer of 0-2 in the formula), Z ₃ represents (i) C ₁ -C ₄ alkyl, (ii) C ₆ -C ₁₀ aryl (may have 1-3 substituted moieties α ₁ ) or (iii) C ₃ -C ₁₀ cycloalkyl, The substituent moiety _α1 represents (i) a C ₁ -C ₄ alkyl group, (ii) a halogen atom, (iii) a hydroxyl group or (iv) an adamantyl group. 41. The α-substituted carboxylic acid derivative, its pharmaceutically acceptable ester or its pharmaceutically acceptable amide or its pharmaceutically acceptable salt according to claim 37, wherein: R ₁ represents a C ₁ -C ₂ alkyl group, R ₂ represents a hydrogen atom, R ₃ represents a C ₁ -C ₄ alkyl group or a phenyl C ₁ -C ₄ alkyl group (the phenyl group may have one substituent α ₁ ), A represents =CH-group, B represents an oxygen atom, W ₁ represents a methylene group, W ₂ represents a methylene group, X represents a hydrogen atom, Y represents an oxygen atom or an S(O)p group (p represents an integer of 0-2 in the formula), Z ₃ represents phenyl (may have 1-3 substituted moieties α ₁ ), The substituent moiety α ₁ represents C ₁ -C ₄ alkyl or hydroxyl. 42. A medicament comprising the compound according to any one of claims 37-41 as an active ingredient. 43. Insulin resistance improvers, blood sugar lowering agents, immunomodulators, aldose reductase inhibitors, 5-lipoxygenase inhibitors, lipid peroxidation production inhibitors, PPAR activators, leukotriene antagonists, hydroxyl An adipocyteization accelerator or a calcium antagonist comprising the compound according to any one of claims 37-41 as an active ingredient. 44. A preventive and/or therapeutic drug for diabetes, glucose intolerance, neuropathy, cataract, coronary artery disease, gestational diabetes, said drug comprising the compound according to any one of claims 37-41 as an active ingredient. 45. Insulin resistance improvers, blood sugar lowering agents, immunomodulators, aldose reductase inhibitors, 5-lipoxygenase inhibitors, lipid peroxidation production inhibitors, PPAR activators, leukotriene antagonists, hydroxyl Adipocyteization promoter or calcium antagonist, the agent contains α-substituted carboxylic acid derivatives having general formula (IV), pharmaceutically acceptable esters thereof or pharmaceutically acceptable amides thereof or pharmaceutically acceptable accepted salt as an active ingredient,

in: R ₁ , R ₂ and R ₃ are the same or different, and represent (i) hydrogen atom, (ii) C ₁ -C ₆ alkyl group, (iii) C ₆ -C ₁₀ aryl group (may have 1-5 following substitutions moiety α ₁ ), (iv) C ₇ -C ₁₆ aralkyl (the aryl group may have 1-5 substituent moieties α ₁ described below), (v) C ₁ -C ₆ alkylsulfonyl, (vi ) C ₁ -C ₆ haloalkylsulfonyl, (vii) C ₆ -C ₁₀ arylsulfonyl (may have 1-5 substituents α ₁ ) or (viii) C ₇ -C ₁₆ aralkylsulfonyl an acyl group (the aryl group may have 1-5 substituent moieties α ₁ described below), R ₄ represents (i) C ₁ -C ₆ alkyl, (ii) C ₆ -C ₁₀ aryl (may have 1-5 substituents α ₁ described below) or (iii) C ₇ -C ₁₆ aralkyl (the aryl group may have 1-5 substituents α ₁ described below), A represents a nitrogen atom or =CH-group, B represents an oxygen atom or a sulfur atom, W ₁ represents a C ₁ -C ₈ alkylene group, W ₂ represents a single bond or a C ₁ -C ₈ alkylene group, X represents (i) hydrogen atom, (ii) C ₁ -C ₆ alkyl, (iii) C ₁ -C ₆ haloalkyl, (iv) C ₁ -C ₆ alkoxy, (v) halogen atom, (vi ) hydroxyl group, (vii) cyano group, (viii) nitro group, (ix) C ₃ -C ₁₀ cycloalkyl group, (x) C ₆ -C ₁₀ aryl group (may have 1-5 substituent moieties β as follows) , (xi) C ₇ -C ₁₆ aralkyl (the aryl may have 1-5 substituents β as described below), (xii) C ₁ -C ₇ aliphatic acyl, (xiii) C ₄ -C ₁₁ Cycloalkylcarbonyl, ((xiv) C ₇ -C ₁₁ arylcarbonyl (may have 1-5 following substituent moieties β), (xv) C ₈ -C ₁₇ aralkylcarbonyl (may have 1-5 of the following substituent moieties β), (xvi) monocyclic heteroaryl ring carbonyl (may have 1-5 of the following substituting moieties β), (xvii) carbamoyl, (xviii) C ₇ -C ₁₁ arylaminocarbonyl (the aryl group may have 1-5 substituents β below) or (xix) amino (can have 1 or 2 substituents β below), Y represents an oxygen atom or an S(O)p group (p represents an integer of 0-2 in the formula), Z ₄ represents (i) C ₁ -C ₆ alkoxyl group, (ii) C ₁ -C ₆ alkylthio group, (iii) halogen atom, (iv) C ₆ -C ₁₀ aryl group (can have 1-5 The following substituent moieties α ₁ ), (v) C ₇ -C ₁₆ aralkyl groups (the aryl group may have 1-5 substituent moieties α ₁ ), (vi) C ₆ -C ₁₀ aryloxy groups ( may have 1 to 5 of the following substituents α ₁ ), (vii) C ₇ -C ₁₆ aralkyloxy (may have 1 to 5 of the following substituents α ₁ on the aryl group), (viii) C ₃ -C ₁₀ cycloalkoxy, (ix) C ₃ -C ₁₀ cycloalkylthio, (x) saturated heterocyclic oxy group (may have 1 to 5 substituents α ₁ ), (xi) monocyclic type The heteroaryl epoxy group (may have 1-5 substituents α ₁ described below), (xii) C ₆ -C ₁₀ arylthio group (may have 1-5 substituents α ₁ described below), (xiii) C ₇ -C ₁₆ aralkylthio (the aryl group may have 1-5 substituents α ₁ described below), (xiv) saturated heterocyclic thio group (may have 1-5 substituents α ₁ described below) , (xv) monocyclic heteroaryl ring thio group (may have 1 to 5 substituents α ₁ described below), (xvi) amino group (may have 1 or 2 substituents α ₁ described below), or (xvii) hydroxyl, The substituent moiety _α1 represents (i) C ₁ -C ₆ alkyl, (ii) C ₁ -C ₆ haloalkyl, (iii) C ₁ -C ₆ alkoxy, (iv) halogen atom, (v) hydroxyl, (vi) cyano group, (vii) nitro group, (viii) C ₃ -C ₁₀ cycloalkyl group, (ix) C ₆ -C ₁₀ aryl group (may have 1-5 substituent moieties β as follows), (x ) C ₇ -C ₁₆ aralkyl group (the aryl group may have 1-5 substituents β as described below), (xi) C ₁ -C ₇ aliphatic acyl group, (xii) C ₄ -C ₁₁ cycloalkyl group Carbonyl, (xiii) C ₇ -C ₁₁ aryl carbonyl (may have 1-5 following substituent moieties β), (xiv) C ₈ -C ₁₇ aralkylcarbonyl (may have 1-5 on aryl The following substituent moiety β), (xv) monocyclic type heteroaryl ring carbonyl (may have 1 to 5 substituent moieties β below), (xvi) carbamoyl group, (xvii) C ₇ -C ₁₁ arylamino group Carbonyl (may have 1-5 substituents β below on the aryl group), (xviii) amino (may have 1 or 2 substituents β below) or (xix) carboxyl, Substituent moiety β represents (i) C ₁ -C ₁₀ alkyl group, (ii) halogen atom, (iii) C ₆ -C ₁₀ aryl group (may have 1-5 substituent moieties γ below), (iv) C ₇ -C ₁₆ aralkyl (can have 1-5 following substituents γ on aryl), (v) C ₁ -C ₇ aliphatic acyl, (vi) C ₇ -C ₁₁ arylcarbonyl (can have 1 - 5 substituent moieties γ described below), (vii) C ₈ -C ₁₇ aralkylcarbonyl (the aryl group may have 1-5 substituent moieties γ described below), (viii) C ₄ -C ₁₁ cycloalkane (ix) monocyclic heteroaryl ring carbonyl (may have 1-5 substituents γ as follows), (x) carbamoyl or (xi) C ₇ -C ₁₁ arylaminocarbonyl (in aromatic The base can have 1-5 substituent moieties γ) as follows, The substituent moiety γ represents a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group, a halogen atom or a hydroxyl group. 46. The agent for improving insulin resistance and blood sugar containing α-substituted carboxylic acid derivatives, their pharmaceutically acceptable esters, their pharmaceutically acceptable amides, or their pharmaceutically acceptable salts as an active ingredient according to claim 45. Lowering agents, immunomodulators, aldose reductase inhibitors, 5-lipoxygenase inhibitors, lipid peroxidation production inhibitors, PPAR activators, leukotriene antagonists, hydroxyadipocyteization promoters, or calcium antagonists ,in: R ₄ represents C ₁ -C ₄ alkyl or phenyl (may have 1-3 substituted moieties α ₁ ). 47. The agent for improving insulin resistance and blood sugar containing α-substituted carboxylic acid derivatives, their pharmaceutically acceptable esters, their pharmaceutically acceptable amides, or their pharmaceutically acceptable salts as an active ingredient according to claim 45. Lowering agents, immunomodulators, aldose reductase inhibitors, 5-lipoxygenase inhibitors, lipid peroxidation production inhibitors, PPAR activators, leukotriene antagonists, hydroxyadipocyteization promoters, or calcium antagonists , wherein R ₄ represents phenyl (may have one substituent α ₁ ). 48. The insulin resistance improving agent containing α-substituted carboxylic acid derivatives, their pharmaceutically acceptable esters or their pharmaceutically acceptable amides or their pharmaceutically acceptable salts as active ingredients according to claims 45-47 , hypoglycemic agents, immunomodulators, aldose reductase inhibitors, 5-lipoxygenase inhibitors, lipid peroxidation production inhibitors, PPAR activators, leukotriene antagonists, hydroxyl adipocyteization promoters, or calcium Antagonists, of which: Z ₄ represents (i) C ₁ -C ₄ alkoxy, (ii) C ₁ -C ₂ alkylthio, (iii) phenoxy (may have 1-3 substituted moieties α ₁ ) or (iv) benzene Thio (may have 1-3 substituent moieties α ₁ ). 49. The insulin resistance improving agent containing α-substituted carboxylic acid derivatives, their pharmaceutically acceptable esters or their pharmaceutically acceptable amides or their pharmaceutically acceptable salts as an active ingredient according to claims 45-47 , hypoglycemic agents, immunomodulators, aldose reductase inhibitors, 5-lipoxygenase inhibitors, lipid peroxidation production inhibitors, PPAR activators, leukotriene antagonists, hydroxyl adipocyteization promoters, or calcium Antagonist, wherein Z ₄ represents C ₁ -C ₂ alkoxy. 50. The insulin resistance improving agent containing α-substituted carboxylic acid derivatives, their pharmaceutically acceptable esters or their pharmaceutically acceptable amides or their pharmaceutically acceptable salts as an active ingredient according to claims 45-47 , hypoglycemic agents, immunomodulators, aldose reductase inhibitors, 5-lipoxygenase inhibitors, lipid peroxidation production inhibitors, PPAR activators, leukotriene antagonists, hydroxyl adipocyteization promoters, or calcium Antagonists wherein Z ₄ represents phenoxy (may have 1-3 substituted moieties α ₁ ). 51. The agent for improving insulin resistance and blood sugar containing α-substituted carboxylic acid derivatives, their pharmaceutically acceptable esters, their pharmaceutically acceptable amides, or their pharmaceutically acceptable salts as an active ingredient according to claim 45. Lowering agents, immunomodulators, aldose reductase inhibitors, 5-lipoxygenase inhibitors, lipid peroxidation production inhibitors, PPAR activators, leukotriene antagonists, hydroxyadipocyteization promoters, or calcium antagonists ,in: R ₁ represents a C ₁ -C ₂ alkyl group, R ₂ represents a hydrogen atom, R ₃ represents a hydrogen atom, R ₄ represents phenyl (may have one substituent α ₁ ), A represents =CH-group, B represents an oxygen atom, W ₁ represents a methylene group, W ₂ represents a methylene group, X represents a hydrogen atom, Z ₄ represents C ₁ -C ₂ alkoxy, The substituent moiety _α1 represents a benzoyl group. 52. The agent for improving insulin resistance and blood sugar containing α-substituted carboxylic acid derivatives, their pharmaceutically acceptable esters, their pharmaceutically acceptable amides, or their pharmaceutically acceptable salts as an active ingredient according to claim 43. Lowering agents, immunomodulators, aldose reductase inhibitors, 5-lipoxygenase inhibitors, lipid peroxidation production inhibitors, PPAR activators, leukotriene antagonists, hydroxyadipocyteization promoters, or calcium antagonists ,in: R ₁ represents a C ₁ -C ₂ alkyl group, R ₂ represents a hydrogen atom, R ₃ represents a hydrogen atom, R ₄ represents phenyl (may have one substituent α ₁ ), A represents =CH-group, B represents an oxygen atom, W ₁ represents a methylene group, W ₂ represents a methylene group, X represents a hydrogen atom, Z ₄ represents phenoxy (may have 1-3 substituent moieties α ₁ ), The substituent moiety _α1 represents a C ₁ -C ₄ alkyl, benzoyl or amino group (may have 1 substituent moiety β), The substituent β represents a phenylaminocarbonyl group (one substituent γ may be present on the phenyl group), The substituent moiety γ represents a trifluoromethyl group. 53. The α-substituted carboxylic acid derivative, its pharmaceutically acceptable ester or its pharmaceutically acceptable amide or its pharmaceutically acceptable salt according to claims 1-52, said α-substituted carboxylic acid derivative selected from: 3-[4-[6-(4-adamantan-1-ylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2-(4-fluoro Benzyloxy)propionic acid, 3-[4-[6-(3,5-di-tert-butyl-4-hydroxyphenylthio)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2- (4-fluorobenzyloxy)propanoic acid, 4-[6-(3,5-di-tert-butyl-4-hydroxyphenylthio)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyllactic acid, 4-[6-(4-Hydroxy-2,3,5-trimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyllactic acid, 4-(1-Methyl-6-methoxy-1H-benzimidazol-2-ylmethoxy)phenyllactic acid, 2-ethoxy-3-[4-(1-methyl-6-methoxy-1H-benzimidazol-2-ylmethoxy)phenyl]propanoic acid, N-(2-benzoylphenyl)-4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenylalanine, 4-[6-(4-Amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]-N-(2-benzoylbenzene base) phenylalanine, 4-[6-[4-(4-trifluoromethylphenylureido)-3,5-dimethylphenoxy]-1-methyl-1H-benzimidazol-2-ylmethoxy ]-N-(2-benzoylphenyl)phenylalanine, 3-[4-(6-Methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-mercaptopropionic acid, 3-[4-(6-Methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionic acid, 3-[4-(6-Methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylsulfinylpropionic acid, 3-[4-(6-Methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylsulfonylpropionic acid, 3-[4-(6-Hydroxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionic acid, 3-[4-[6-(β-D-glucopyranosyloxyuronic acid)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2-methyl Thiopropionic acid, 3-[4-(1-Methyl-6-methylthio-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionic acid, 3-[4-(1-Methyl-6-methylthio-1H-benzimidazol-2-ylmethoxy)phenyl]-2-mercaptopropionic acid. 54. The α-substituted carboxylic acid derivative, its pharmaceutically acceptable ester or its pharmaceutically acceptable amide or its pharmaceutically acceptable salt according to claims 1-52, said α-substituted carboxylic acid derivative selected from: 3-[4-[6-(4-adamantan-1-ylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2-(4-fluoro Benzyloxy)propionic acid, 3-[4-[6-(3,5-di-tert-butyl-4-hydroxyphenylthio)-1-methyl-1H-benzimidazol-2-ylmethoxy]phenyl]-2- (4-fluorobenzyloxy)propanoic acid, 2-ethoxy-3-[4-(1-methyl-6-methoxy-1H-benzimidazol-2-ylmethoxy)phenyl]propanoic acid, N-(2-benzoylphenyl)-4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenylalanine, 4-[6-(4-Amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]-N-(2-benzoylbenzene base) phenylalanine, 3-[4-(6-Methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylsulfinylpropionic acid, 3-[4-(1-Methyl-6-methylthio-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropanoic acid. 55. A medicament comprising the compound according to any one of claims 53 and 54 as an active ingredient. 56. Insulin resistance improvers, blood sugar lowering agents, immunomodulators, aldose reductase inhibitors, 5-lipoxygenase inhibitors, lipid peroxidation production inhibitors, PPAR activators, leukotriene antagonists, hydroxyl An adipocyteization accelerator or a calcium antagonist comprising the compound according to any one of claims 53 and 54 as an active ingredient. 57. A preventive and/or therapeutic drug for diabetes, glucose intolerance, neuropathy, cataract, coronary artery disease, gestational diabetes, said drug comprising the compound according to any one of claims 53 and 54 as an active ingredient. 58. The insulin resistance improving agent according to any one of claims 1-26, 35, 43, 45-52 and 56. 59. The blood glucose lowering agent of any one of claims 1-26, 35, 43, 45-52 and 56. 60. Preventive and/or therapeutic drugs for diabetes, glucose intolerance, neuropathy, cataract, coronary artery disease, and gestational diabetes, which contain α-substituted carboxylic acid derivatives with general formula (I), pharmaceutically acceptable Esters or their pharmaceutically acceptable amides or their pharmaceutically acceptable salts as active ingredients,

in: R ₁ , R ₂ and R ₃ are the same or different, and represent (i) hydrogen atom, (ii) C ₁ -C ₆ alkyl group, (iii) C ₆ -C ₁₀ aryl group (may have 1-5 following substitutions moiety α ₁ ), (iv) C ₇ -C ₁₆ aralkyl (the aryl group may have 1-5 substituent moieties α ₁ described below), (v) C ₁ -C ₆ alkylsulfonyl, (vi ) C ₁ -C ₆ haloalkylsulfonyl, (vii) C ₆ -C ₁₀ arylsulfonyl (may have 1-5 substituents α ₁ ) or (viii) C ₇ -C ₁₆ aralkylsulfonyl an acyl group (the aryl group may have 1-5 substituent moieties α ₁ described below), A represents a nitrogen atom or =CH-group, B represents an oxygen atom or a sulfur atom, W ₁ represents a C ₁ -C ₈ alkylene group, W ₂ represents a single bond or a C ₁ -C ₈ alkylene group, X represents (i) hydrogen atom, (ii) C ₁ -C ₆ alkyl, (iii) C ₁ -C ₆ haloalkyl, (iv) C ₁ -C ₆ alkoxy, (v) halogen atom, (vi ) hydroxyl group, (vii) cyano group, (viii) nitro group, (ix) C ₃ -C ₁₀ cycloalkyl group, (x) C ₆ -C ₁₀ aryl group (may have 1-5 substituent moieties β as follows) , (xi) C ₇ -C ₁₆ aralkyl (the aryl may have 1-5 substituents β as described below), (xii) C ₁ -C ₇ aliphatic acyl, (xiii) C ₄ -C ₁₁ Cycloalkylcarbonyl, (xiv) C ₇ -C ₁₁ arylcarbonyl (may have 1-5 following substituent moieties β), (xv) C ₈ -C ₁₇ aralkylcarbonyl (may have 1 on aryl -5 substituent moieties β below), (xvi) monocyclic heteroaryl ring carbonyl (may have 1 to 5 substituent moieties β below), (xvii) carbamoyl, (xviii) C ₇ -C ₁₁ Arylaminocarbonyl (the aryl group may have 1-5 substituents β below) or (xix) amino (can have 1 or 2 substituents β below), Y represents an oxygen atom or an S(O)p group (p represents an integer of 0-2 in the formula), Z ₁ represents (i) hydrogen atom, (ii) C ₁ -C ₆ alkyl group, (iii) C ₁ -C ₆ alkoxy group, (iv) C ₁ -C ₆ alkylthio group, (v) halogen atom, (vi) C ₆ -C ₁₀ aryl (may have 1-5 substituents α ₁ described below), (vii) C ₇ -C ₁₆ aralkyl (may have 1-5 substituents described below on aryl Moiety α ₁ ), (viii) C ₆ -C ₁₀ aryloxy group (may have 1-5 substituent moieties α ₁ described below), (ix) C ₇ -C ₁₆ aralkyloxy group (may have 1-5 of the following substituted moieties α ₁ ), (x) C ₃ -C ₁₀ cycloalkoxy, (xi) C ₃ -C ₁₀ cycloalkylthio, (xii) saturated heterocyclic oxy group (may have 1 -5 substituted moieties α ₁ ), (xiii) monocyclic heteroaryl epoxy group (may have 1-5 substituted moieties α ₁ ), (xiv) C ₆ -C ₁₀ arylthio ( may have 1 to 5 of the following substituent moieties α ₁ ), (xv) C ₇ -C ₁₆ aralkylthio (may have 1 to 5 of the following substituent moieties α ₁ on the aryl group), (xvi) saturated hetero Cyclothio group (may have 1 to 5 substituents α ₁ described below), (xvii) monocyclic heteroaryl ring thio group (may have 1 to 5 substituents α ₁ described below), (xviii) amino ( may have 1 or 2 of the following substituted moieties (α ₁ ) or (xix) hydroxyl groups, The substituent moiety _α1 represents (i) C ₁ -C ₆ alkyl, (ii) C ₁ -C ₆ haloalkyl, (iii) C ₁ -C ₆ alkoxy, (iv) halogen atom, (v) hydroxyl, (vi) cyano group, (vii) nitro group, (viii) C ₃ -C ₁₀ cycloalkyl group, (ix) C ₆ -C ₁₀ aryl group (may have 1-5 substituent moieties β as follows), (x ) C ₇ -C ₁₆ aralkyl group (the aryl group may have 1-5 substituents β as described below), (xi) C ₁ -C ₇ aliphatic acyl group, (xii) C ₄ -C ₁₁ cycloalkyl group Carbonyl, (xiii) C ₇ -C ₁₁ aryl carbonyl (may have 1-5 following substituent moieties β), (xiv) C ₈ -C ₁₇ aralkylcarbonyl (may have 1-5 on aryl The following substituent moiety β), (xv) monocyclic type heteroaryl ring carbonyl (may have 1 to 5 substituent moieties β below), (xvi) carbamoyl group, (xvii) C ₇ -C ₁₁ arylamino group Carbonyl (may have 1-5 substituents β below on the aryl group), (xviii) amino (may have 1 or 2 substituents β below) or (xix) carboxyl, Substituent moiety β represents (i) C ₁ -C ₁₀ alkyl group, (ii) halogen atom, (iii) C ₆ -C ₁₀ aryl group (may have 1-5 substituent moieties γ below), (iv) C ₇ -C ₁₆ aralkyl (can have 1-5 following substituents γ on aryl), (v) C ₁ -C ₇ aliphatic acyl, (vi) C ₇ -C ₁₁ arylcarbonyl (can have 1 - 5 substituent moieties γ described below), (vii) C ₈ -C ₁₇ aralkylcarbonyl (the aryl group may have 1-5 substituent moieties γ described below), (viii) C ₄ -C ₁₁ cycloalkane (ix) monocyclic heteroaryl ring carbonyl (may have 1-5 substituents γ as follows), (x) carbamoyl or (xi) C ₇ -C ₁₁ arylaminocarbonyl (in aromatic The base may have 1-5 substituent moieties γ) as follows, The substituent moiety γ represents a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group, a halogen atom or a hydroxyl group. 61. Preventive and/or therapeutic drugs for diabetes, glucose intolerance, neuropathy, cataract, coronary artery disease, and gestational diabetes, which contain α-substituted carboxylic acid derivatives with general formula (Iv), pharmaceutically acceptable Esters or their pharmaceutically acceptable amides or their pharmaceutically acceptable salts as active ingredients,

in: R ₁ , R ₂ and R ₃ are the same or different, and represent (i) hydrogen atom, (ii) C ₁ -C ₆ alkyl group, (iii) C ₆ -C ₁₀ aryl group (may have 1-5 following substitutions moiety α ₁ ), (iv) C ₇ -C ₁₆ aralkyl (the aryl group may have 1-5 substituent moieties α ₁ described below), (v) C ₁ -C ₆ alkylsulfonyl, (vi ) C ₁ -C ₆ haloalkylsulfonyl, (vii) C ₆ -C ₁₀ arylsulfonyl (may have 1-5 substituents α ₁ ) or (viii) C ₇ -C ₁₆ aralkylsulfonyl an acyl group (the aryl group may have 1-5 substituent moieties α ₁ described below), R ₄ represents (i) C ₁ -C ₆ alkyl, (ii) C ₆ -C ₁₀ aryl (may have 1-5 substituents α ₁ described below) or (iii) C ₇ -C ₁₆ aralkyl (the aryl group may have 1-5 substituents α ₁ described below), A represents a nitrogen atom or =CH-group, B represents an oxygen atom or a sulfur atom, W ₁ represents a C ₁ -C ₈ alkylene group, W ₂ represents a single bond or a C ₁ -C ₈ alkylene group, X represents (i) hydrogen atom, (ii) C ₁ -C ₆ alkyl, (iii) C ₁ -C ₆ haloalkyl, (iv) C ₁ -C ₆ alkoxy, (v) halogen atom, (vi ) hydroxyl group, (vii) cyano group, (viii) nitro group, (ix) C ₃ -C ₁₀ cycloalkyl group, (x) C ₆ -C ₁₀ aryl group (may have 1-5 substituent moieties β as follows) , (xi) C ₇ -C ₁₆ aralkyl (the aryl may have 1-5 substituents β as described below), (xii) C ₁ -C ₇ aliphatic acyl, (xiii) C ₄ -C ₁₁ Cycloalkylcarbonyl, (xiv) C ₇ -C ₁₁ arylcarbonyl (may have 1-5 following substituent moieties β), (xv) C ₈ -C ₁₇ aralkylcarbonyl (may have 1 on aryl -5 substituent moieties β below), (xvi) monocyclic heteroaryl ring carbonyl (may have 1 to 5 substituent moieties β below), (xvii) carbamoyl, (xviii) C ₇ -C ₁₁ Arylaminocarbonyl (the aryl group may have 1-5 substituents β below) or (xix) amino (can have 1 or 2 substituents β below), Y represents an oxygen atom or an S(O)p group (p represents an integer of 0-2 in the formula), Z ₄ represents (i) C ₁ -C ₆ alkoxyl group, (ii) C ₁ -C ₆ alkylthio group, (iii) halogen atom, (iv) C ₆ -C ₁₀ aryl group (can have 1-5 The following substituent moieties α ₁ ), (v) C ₇ -C ₁₆ aralkyl groups (the aryl group may have 1-5 substituent moieties α ₁ ), (vi) C ₆ -C ₁₀ aryloxy groups ( may have 1 to 5 of the following substituents α ₁ ), (vii) C ₇ -C ₁₆ aralkyloxy (may have 1 to 5 of the following substituents α ₁ on the aryl group), (viii) C ₃ -C ₁₀ cycloalkoxy, (ix) C ₃ -C ₁₀ cycloalkylthio, (x) saturated heterocyclic oxy group (may have 1 to 5 substituents α ₁ ), (xi) monocyclic type The heteroaryl epoxy group (may have 1-5 substituent moieties α ₁ described below), (xii) C ₆ -C ₁₀ arylthio group (may have 1-5 substituent moieties α ₁ described below), (xiii) C ₇ -C ₁₆ aralkylthio (the aryl group may have 1-5 substituents α ₁ described below), (xiv) saturated heterocyclic thio group (may have 1-5 substituents α ₁ described below) , (xv) monocyclic heteroaryl ring thio group (may have 1 to 5 substituents α ₁ described below), (xvi) amino group (may have 1 or 2 substituents α ₁ described below), or (xvii) hydroxyl, The substituent moiety _α1 represents (i) C ₁ -C ₆ alkyl, (ii) C ₁ -C ₆ haloalkyl, (iii) C ₁ -C ₆ alkoxy, (iv) halogen atom, (v) hydroxyl, (vi) cyano group, (vii) nitro group, (viii) C ₃ -C ₁₀ cycloalkyl group, (ix) C ₆ -C ₁₀ aryl group (may have 1-5 substituent moieties β as follows), (x ) C ₇ -C ₁₆ aralkyl group (the aryl group may have 1-5 substituents β as described below), (xi) C ₁ -C ₇ aliphatic acyl group, (xii) C ₄ -C ₁₁ cycloalkyl group Carbonyl, (xiii) C ₇ -C ₁₁ aryl carbonyl (may have 1-5 following substituent moieties β), (xiv) C ₈ -C ₁₇ aralkylcarbonyl (may have 1-5 on aryl The following substituent moiety β), (xv) monocyclic type heteroaryl ring carbonyl (may have 1 to 5 substituent moieties β below), (xvi) carbamoyl group, (xvii) C ₇ -C ₁₁ arylamino group Carbonyl (may have 1-5 substituents β below on the aryl group), (xviii) amino (may have 1 or 2 substituents β below) or (xix) carboxyl, Substituent moiety β represents (i) C ₁ -C ₁₀ alkyl group, (ii) halogen atom, (iii) C ₆ -C ₁₀ aryl group (may have 1-5 substituent moieties γ below), (iv) C ₇ -C ₁₆ aralkyl (can have 1-5 following substituents γ on aryl), (v) C ₁ -C ₇ aliphatic acyl, (vi) C ₇ -C ₁₁ arylcarbonyl (can have 1 - 5 substituent moieties γ described below), (vii) C ₈ -C ₁₇ aralkylcarbonyl (the aryl group may have 1-5 substituent moieties γ described below), (viii) C ₄ -C ₁₁ cycloalkane (ix) monocyclic heteroaryl ring carbonyl (may have 1-5 substituents γ as follows), (x) carbamoyl or (xi) C ₇ -C ₁₁ arylaminocarbonyl (in aromatic The base may have 1-5 substituent moieties γ) as follows, The substituent moiety γ represents a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ haloalkyl group, a halogen atom or a hydroxyl group. 62. A preventive and/or therapeutic drug for diabetes comprising the compound according to any one of claims 36, 44, 57, 60 and 61 as an active ingredient. 63. A pharmaceutical composition comprising the insulin resistance improving agent according to any one of claims 1-26, 35, 43, 45-52 and 56 as an active ingredient. 64. A pharmaceutical composition comprising the blood sugar lowering agent according to any one of claims 1-26, 35, 43, 45-52 and 56 as an active ingredient. 65. A pharmaceutical composition comprising a preventive and/or therapeutic drug for diabetes containing the compound according to any one of claims 36, 44, 57, 60 and 61 as an active ingredient. 66. Use of the compound according to any one of claims 1-26, 35, 43, 45-52 and 56 in the preparation of an agent for improving insulin resistance. 67. Use of the compound according to any one of claims 1-26, 35, 43, 45-52 and 56 in the preparation of a blood sugar lowering agent. 68. Use of the compound according to any one of claims 36, 44, 57, 60 and 61 in the preparation of a drug for the prevention and/or treatment of diabetes.